Therapeutic drug for dyskinesia

ABSTRACT

The present invention provides a therapeutic drug that is useful for levodopa induced dyskinesia in Parkinson&#39;s disease. In particular, the present invention provides a composition and method for treating, improving, suppressing the progression, or preventing motor complications associated with levodopa therapy for Parkinson&#39;s disease, especially levodopa induced dyskinesia (PD-LID), comprising tandospirone or a pharmaceutically acceptable salt or prodrug thereof, wherein the tandospirone or a pharmaceutically acceptable salt or prodrug thereof is parenterally administered.

TECHNICAL FIELD

The present invention relates to a formulation for treating levodopainduced dyskinesia in Parkinson's disease by parenteral administration(e.g., transdermal administration), comprising tandospirone or apharmaceutically acceptable salt or prodrug thereof that is useful as amedicament as an active ingredient.

BACKGROUND ART

Parkinson's disease is a progressive neurodegenerative disease with aprimary symptom of extrapyramidal function abnormality. Pathologically,loss of dopaminergic neurons and alpha-synuclein deposition in thesubstantia nigra pars compacta are observed. Clinically, various motorsymptoms such as akinesia, tremor, rigidity, and loss of posturalreflexes are exhibited.

Parkinson's disease therapy is fundamentally a drug therapy intended tosupplement intracerebral dopamine. A drug comprising levodopa (L-dopa),which is a dopamine precursor, is used as the first-line drug for theinitial therapy of Parkinson's disease. However, motor complicationssuch as Parkinson's Disease Levodopa induced dyskinesia (hereinafter,also referred to as “PD-LID”) are manifested in almost all patientsundergoing levodopa therapy with the progression in pathologicalconditions.

The frequency of developing PD-LID in 5 years after the initial levodopatherapy is 30 to 50%. The frequency increases with the progression ofthe pathological condition and reaches 50 to 100% in 10 years after theinitial therapy. Peak-dose dyskinesia is known as an exemplary symptomof PD-LID, which is an involuntary movement manifested in the face,tongue, neck, limbs, body trunk, or the like when the blood levodopaconcentration is high.

Patent Literature 1 [Japanese Laid-Open Publication No. 11-228414] has adisclosure on transdermally absorbed tandospirone agents.

CITATION LIST Patent Literature

[Patent Literature 1] Japanese Laid-Open Publication No. 11-228414

SUMMARY OF INVENTION Solution to Problem

As a result of diligent studies, the inventors have discovered that auseful technology for treatment, improvement, suppression ofprogression, or prevention with a high effect of improving ofParkinson's disease levodopa induced dyskinesia (PD-LID) or the like canbe provided, as compared to oral administration, by parenterallyadministering (e.g., transdermal administration, intradermaladministration, subcutaneous administration, intramuscularadministration, or the like) tandospirone or a pharmaceuticallyacceptable salt or prodrug thereof. The present invention providestransdermally administered pharmaceutical compositions for improvingPD-LID, comprising tandospirone or a pharmaceutically acceptable salt orprodrug thereof, and methods of treating, improving, suppressing theprogression, and preventing motor complications of Parkinson's diseaseby parenteral administration including tandospirone or apharmaceutically acceptable salt or prodrug thereof.

Specifically, the present invention comprises the following.

-   [Item 1]

A composition for treating, improving, suppressing the progression, orpreventing motor complications associated with levodopa therapy forParkinson's disease, comprising tandospirone or a pharmaceuticallyacceptable salt or prodrug thereof, wherein the tandospirone or apharmaceutically acceptable salt or prodrug thereof is parenterallyadministered.

-   [Item 2]

The composition of any one of the preceding items, wherein theparenteral administration is selected from transdermal administration,intradermal administration, subcutaneous administration, intramuscularadministration, and a combination thereof.

-   [Item 3]

The composition of any one of the preceding items, wherein theparenteral administration has sustainability or is sustainablyadministered.

-   [Item 4]

The composition of any one of the preceding items, wherein theparenteral administration comprises transdermal administration.

-   [Item 5]

The composition of any one of the preceding items, wherein the motorcomplications comprise levodopa induced dyskinesia (PD-LID).

-   [Item 6]

A composition for treating, improving, or preventing motor complicationsassociated with levodopa therapy for Parkinson's disease, comprisingtandospirone or a pharmaceutically acceptable salt or prodrug thereof,wherein levodopa induced dyskinesia (PD-LID) is improved withoutresulting in a rebound symptom, and wherein the tandospirone or apharmaceutically acceptable salt or prodrug thereof is transdermallyadministered.

-   [Item 7]

The composition of any one of the preceding items, wherein levodopainduced dyskinesia (PD-LID) comprises peak-dose dyskinesia, diphasicdyskinesia, and a combination thereof.

-   [Item 8]

The composition of any one of the preceding items, wherein thetreatment, improvement, suppression of progression, or prevention ofmotor complications comprises improvement, suppression of progression,or prevention of a levodopa induced dyskinesia (PD-LID) symptom,reduction of a period of levodopa induced dyskinesia (PD-LID)manifestation, or a combination thereof.

-   [Item 9]

A composition for accomplishing improvement, suppression of progression,or prevention of a levodopa induced dyskinesia (PD-LID) symptom,reduction of a period of levodopa induced dyskinesia (PD-LID)manifestation, or a combination thereof, comprising tandospirone or apharmaceutically acceptable salt or prodrug thereof, wherein thetandospirone or a pharmaceutically acceptable salt or prodrug thereof isparenterally administered.

-   [Item 10]

The composition of any one of the preceding items, wherein theimprovement of a levodopa induced dyskinesia (PD-LID) symptom is aclinically significant improvement or greater.

-   [Item 11]

The composition of any one of the preceding items, wherein theimprovement a levodopa induced dyskinesia (PD-LID) symptom is to asufficient level to attain a clinical effect.

-   [Item 12]

The composition of any one of the preceding items, wherein thecomposition is a transdermally administered formulation.

-   [Item 13]

The composition of any one of the preceding items, wherein thecomposition is an adhesive formulation.

-   [Item 14]

The composition of any one of the preceding items, wherein atransdermally administered formulation is a tape/patch.

-   [Item 15]

The composition of any one of the preceding items, wherein a drug dosageof the tandospirone or a pharmaceutically acceptable salt or prodrugthereof is 0.1 to 100 mg per day as a free form of tandospirone.

-   [Item 16]

The composition of any one of the preceding items, wherein an amount ofdrug penetration for the tandospirone or a pharmaceutically acceptablesalt or prodrug thereof is 0.1 to 20 mg per day as a free form oftandospirone.

-   [Item 17]

The composition of any one of the preceding items, wherein thecomposition is a transdermally administered formulation, and a totalapplied area per dose is 1 to 100 cm².

-   [Item 18]

The composition of any one of the preceding items, wherein thetandospirone or a pharmaceutically acceptable salt or prodrug thereof isadministered so that a human blood (plasma) tandospirone concentrationis 0.05 to 20 ng/mL for 12 hours or longer per day.

-   [Item 19]

The composition of any one of the preceding items, wherein thetandospirone or a pharmaceutically acceptable salt or prodrug thereof isadministered so that a human blood (plasma) tandospirone concentrationis 0.05 to 20 ng/mL for 8 to 16 hours after administration of thetandospirone or a pharmaceutically acceptable salt or prodrug thereof.

-   [Item 20]

The composition of any one of the preceding items, wherein thetandospirone or a pharmaceutically acceptable salt or prodrug thereof isan adjunct of levodopa.

-   [Item 21]

The composition of any one of the preceding items, which is used withlevodopa as the fixed-dose combination or concomitantly as separateformulations.

-   [Item 22]

A medicament for treating or preventing Parkinson's disease withoutaccompanying or by minimizing PD-LID, comprising a combination oftandospirone or a pharmaceutically acceptable salt or prodrug thereofand (1) levodopa or (2) levodopa and a metabolizing enzyme inhibitor oflevodopa, wherein the tandospirone or a pharmaceutically acceptable saltor prodrug thereof is parenterally administered.

-   [Item 23]

A medicament for treating or preventing Parkinson's disease withoutaccompanying or by minimizing PD-LID, comprising tandospirone or apharmaceutically acceptable salt or prodrug thereof, wherein thetandospirone or a pharmaceutically acceptable salt or prodrug thereof isadministered in combination with (1) levodopa or (2) levodopa and ametabolizing enzyme inhibitor of levodopa, wherein the tandospirone or apharmaceutically acceptable salt or prodrug thereof is parenterallyadministered.

-   [Item 24]

A medicament for treating or preventing Parkinson's disease withoutaccompanying or by minimizing PD-LID, comprising (1) levodopa or (2)levodopa and a metabolizing enzyme inhibitor of levodopa, wherein the(1) levodopa or (2) levodopa and a metabolizing enzyme inhibitor oflevodopa is administered in combination with tandospirone or apharmaceutically acceptable salt or prodrug thereof, wherein thetandospirone or a pharmaceutically acceptable salt or prodrug thereof isparenterally administered.

-   [Item 25]

A composition for improving the exacerbation in quality of response tolevodopa therapy of a Parkinson's disease patient with dyskinesia,comprising tandospirone or a pharmaceutically acceptable salt or prodrugthereof, wherein the tandospirone or a pharmaceutically acceptable saltor prodrug thereof is parenterally administered.

-   [Item 26]

The medicament or composition of any one of the preceding items, whereinthe tandospirone or a pharmaceutically acceptable salt or prodrugthereof is a free form of tandospirone.

-   [Item 1A]

A method for treating, improving, or preventing motor complicationsassociated with levodopa therapy for Parkinson's disease, comprisingparenterally administering an effective amount of tandospirone or apharmaceutically acceptable salt or prodrug thereof to a subject.

-   [Item 2A]

The method of any one of the preceding items, wherein the parenteraladministration is selected from transdermal administration, intradermaladministration, subcutaneous administration, intramuscularadministration, and a combination thereof.

-   [Item 3A]

The method of any one of the preceding items, wherein the parenteraladministration has sustainability or is sustainably administered.

-   [Item 4A]

The method of any one of the preceding items, wherein the parenteraladministration comprises transdermal administration.

-   [Item 5A]

The method of any one of the preceding items, wherein the motorcomplications comprise levodopa induced dyskinesia (PD-LID).

-   [Item 6A]

A method of treating, improving, or preventing motor complicationsassociated with levodopa therapy for Parkinson's disease, comprisingtransdermally administering an effective amount of tandospirone or apharmaceutically acceptable salt or prodrug thereof to a subject, suchthat levodopa induced dyskinesia (PD-LID) is improved without a reboundsymptom.

-   [Item 7A]

The method of any one of the preceding items, wherein levodopa induceddyskinesia (PD-LID) comprises peak-dose dyskinesia, diphasic dyskinesia,and a combination thereof.

-   [Item 8A]

The method of any one of the preceding items, wherein the treatment,improvement, suppression of progression, or prevention of motorcomplications comprises improvement, suppression of progression, orprevention of a levodopa induced dyskinesia (PD-LID) symptom, reductionof a period of levodopa induced dyskinesia (PD-LID) manifestation, or acombination thereof.

-   [Item 9A]

A method for accomplishing improvement, suppression of progression, orprevention of a levodopa induced dyskinesia (PD-LID) symptom, reductionof a period of levodopa induced dyskinesia (PD-LID) manifestation, or acombination thereof, comprising parenterally administering an effectiveamount of tandospirone or a pharmaceutically acceptable salt or prodrugthereof to a subject.

-   [Item 10A]

The method of any one of the preceding items, wherein the improvement ofa levodopa induced dyskinesia (PD-LID) symptom is a clinicallysignificant improvement or greater.

-   [Item 11A]

The method of any one of the preceding items, wherein the improvement ofa levodopa induced dyskinesia (PD-LID) symptom is to a sufficient levelto attain a clinical effect.

-   [Item 12A]

The method of any one of the preceding items, wherein the tandospironeor a pharmaceutically acceptable salt or prodrug thereof is provided asa transdermally administered formulation.

-   [Item 13A]

The method of any one of the preceding items, wherein the tandospironeor a pharmaceutically acceptable salt or prodrug thereof is provided asan adhesive formulation.

-   [Item 14A]

The method of any one of the preceding items, wherein the transdermallyadministered formulation is a tape/patch.

-   [Item 15A]

The method of any one of the preceding items, wherein a drug dosage ofthe tandospirone or a pharmaceutically acceptable salt or prodrugthereof is 0.1 to 100 mg per day as a free form of tandospirone.

-   [Item 16A]

The method of any one of the preceding items, wherein an amount of drugpenetration for the tandospirone or a pharmaceutically acceptable saltor prodrug thereof is 0.1 to 20 mg per day as a free form oftandospirone.

-   [Item 17A]

The method of any one of the preceding items, wherein the administrationis accomplished with a transdermally administered formulation, and atotal applied area per dose is 1 to 100 cm².

-   [Item 18A]

The method of any one of the preceding items, wherein the tandospironeor a pharmaceutically acceptable salt or prodrug thereof is administeredso that a human blood (plasma) tandospirone concentration is 0.05 to 20ng/mL for 12 hours or longer per day.

-   [Item 19A]

The method of any one of the preceding items, wherein the tandospironeor a pharmaceutically acceptable salt or prodrug thereof is administeredso that a human blood (plasma) tandospirone concentration is 0.05 to 20ng/mL for 8 to 16 hours after administration of the tandospirone or apharmaceutically acceptable salt or prodrug thereof.

-   [Item 20A]

The method of any one of the preceding items, wherein the tandospironeor a pharmaceutically acceptable salt or prodrug thereof is an adjunctof levodopa.

-   [Item 21A]

The method of any one of the preceding items, wherein the tandospironeor a pharmaceutically acceptable salt or prodrug thereof is used withlevodopa as the fixed-dose combination or concomitantly as separateformulations.

-   [Item 22A]

A method for treating or preventing Parkinson's disease withoutaccompanying or by minimizing PD-LID in a subject, comprisingadministering to the subject an effective amount of a combination of aneffective amount of tandospirone or a pharmaceutically acceptable saltor prodrug thereof and (1) an effective amount of levodopa or (2)levodopa and a metabolizing enzyme inhibitor of levodopa, wherein theeffective amount of tandospirone or a pharmaceutically acceptable saltor prodrug thereof is parenterally administered.

-   [Item 23A]

The method of any one of the preceding items, wherein the tandospironeor a pharmaceutically acceptable salt or prodrug thereof and the (1) or(2) are administered simultaneously or at different times.

-   [Item 24A]

A composition for improving the exacerbation in quality of response tolevodopa therapy of a Parkinson's disease patient with dyskinesia,comprising tandospirone or a pharmaceutically acceptable salt or prodrugthereof, wherein an effective amount of the tandospirone or apharmaceutically acceptable salt or prodrug thereof is parenterallyadministered.

-   [Item 25A]

The method of any one of the preceding items, wherein the tandospironeor a pharmaceutically acceptable salt thereof is a free form oftandospirone.

-   [Item 1B]

Use of tandospirone or a pharmaceutically acceptable salt or prodrugthereof in the manufacture of a medicament for treating, improving, orpreventing motor complications associated with levodopa therapy forParkinson's disease, wherein the medicament is parenterallyadministered.

-   [Item 2B]

The use of any one of the preceding items, wherein the parenteraladministration is selected from transdermal administration, intradermaladministration, subcutaneous administration, intramuscularadministration, and a combination thereof.

-   [Item 3B]

The use of any one of the preceding items, wherein the parenteraladministration has sustainability or is sustainably administered.

-   [Item 4B]

The use of any one of the preceding items, wherein the parenteraladministration comprises transdermal administration.

-   [Item 5B]

The use of any one of the preceding items, wherein the motorcomplications comprise levodopa induced dyskinesia (PD-LID).

-   [Item 6B]

Use in the manufacture of a medicament comprising tandospirone or apharmaceutically acceptable salt or prodrug thereof for the treatment,improvement, or prevention of motor complications associated withlevodopa therapy for Parkinson's disease, wherein levodopa induceddyskinesia (PD-LID) is improved without resulting in a rebound symptom,and wherein the tandospirone or a pharmaceutically acceptable salt orprodrug thereof is transdermally administered.

-   [Item 7B]

The use of any one of the preceding items, wherein levodopa induceddyskinesia (PD-LID) comprises peak-dose dyskinesia, diphasic dyskinesia,and a combination thereof.

-   [Item 8B]

The use of any one of the preceding items, wherein the treatment,improvement, suppression of progression, or prevention of motorcomplications comprises improvement, suppression of progression, orprevention of a levodopa induced dyskinesia (PD-LID) symptom, reductionof a period of levodopa induced dyskinesia (PD-LID) manifestation, or acombination thereof.

-   [Item 9B]

Use in the manufacture of a medicament comprising tandospirone or apharmaceutically acceptable salt or prodrug thereof for accomplishingthe improvement, suppression of progression, or prevention of a levodopainduced dyskinesia (PD-LID) symptom, reduction of a period of levodopainduced dyskinesia (PD-LID) manifestation, or a combination thereof,wherein the tandospirone or a pharmaceutically acceptable salt orprodrug thereof is parenterally administered.

-   [Item 10B]

The use of any one of the preceding items, wherein the improvement of alevodopa induced dyskinesia (PD-LID) symptom is a clinically significantimprovement or greater.

-   [Item 11B]

The use of any one of the preceding items, wherein the improvement of alevodopa induced dyskinesia (PD-LID) symptom is to a sufficient level toattain a clinical effect.

-   [Item 12B]

The use of any one of the preceding items, wherein the medicament is atransdermally administered formulation.

-   [Item 13B]

The use of any one of the preceding items, wherein the medicament is anadhesive formulation.

-   [Item 14B]

The use of any one of the preceding items, wherein the transdermallyadministered formulation is a tape/patch.

-   [Item 15B]

The use of any one of the preceding items, wherein a drug dosage of thetandospirone or a pharmaceutically acceptable salt or prodrug thereof is0.1 to 100 mg per day as a free form of tandospirone.

-   [Item 16B]

The use of any one of the preceding items, wherein an amount of drugpenetration for the tandospirone or a pharmaceutically acceptable saltor prodrug thereof is 0.1 to 20 mg per day as a free form oftandospirone.

-   [Item 17B]

The use of any one of the preceding items, wherein the medicament is atransdermally administered formulation, and a total applied area perdose is 1 to 100 cm².

-   [Item 18B]

The use of any one of the preceding items, wherein the tandospirone or apharmaceutically acceptable salt or prodrug thereof is administered sothat a human blood (plasma) tandospirone concentration is 0.05 to 20ng/mL for 12 hours or longer per day.

-   [Item 19B]

The use of any one of the preceding items, wherein the tandospirone or apharmaceutically acceptable salt or prodrug thereof is administered sothat a human blood (plasma) tandospirone concentration is 0.05 to 20ng/mL for 8 to 16 hours after administration of the tandospirone or apharmaceutically acceptable salt or prodrug thereof.

-   [Item 20B]

The use of any one of the preceding items, wherein the tandospirone or apharmaceutically acceptable salt or prodrug thereof is an adjunct oflevodopa.

-   [Item 21B]

The use of any one of the preceding items, wherein the medicament isused with levodopa as the fixed-dose combination or concomitantly asseparate formulations.

-   [Item 22B]

Use in the manufacture of a medicament for treating or preventingParkinson's disease without accompanying or by minimizing PD-LID,wherein the medicament comprises a combination of tandospirone or apharmaceutically acceptable salt or prodrug thereof and (1) levodopa or(2) levodopa and a metabolizing enzyme inhibitor of levodopa, whereinthe tandospirone or a pharmaceutically acceptable salt or prodrugthereof is parenterally administered.

-   [Item 23B]

Use in the manufacture of a medicament for treating or preventingParkinson's disease without accompanying or by minimizing PD-LID,wherein the medicament comprises tandospirone or a pharmaceuticallyacceptable salt or prodrug thereof, wherein the tandospirone or apharmaceutically acceptable salt or prodrug thereof is administered incombination with (1) levodopa or (2) levodopa and a metabolizing enzymeinhibitor of levodopa, wherein the tandospirone or a pharmaceuticallyacceptable salt or prodrug thereof is parenterally administered.

-   [Item 24B]

Use in the manufacture of a medicament for treating or preventingParkinson's disease without accompanying or by minimizing PD-LID,wherein the medicament comprises (1) levodopa or (2) levodopa and ametabolizing enzyme inhibitor of levodopa, wherein the (1) levodopa or(2) levodopa and a metabolizing enzyme inhibitor of levodopa isadministered in combination with tandospirone or a pharmaceuticallyacceptable salt or prodrug thereof, and wherein the tandospirone or apharmaceutically acceptable salt or prodrug thereof is parenterallyadministered.

-   [Item 25B]

Use in the manufacture of a medicament comprising tandospirone or apharmaceutically acceptable salt or prodrug thereof for improving theexacerbation in quality of response to levodopa therapy of a Parkinson'sdisease patient with dyskinesia, wherein the tandospirone or apharmaceutically acceptable salt or prodrug thereof is parenterallyadministered.

-   [Item 26B]

The use of any one of the preceding items, wherein the tandospirone or apharmaceutically acceptable salt thereof is a free form of tandospirone.

-   [Item 1C]

Tandospirone or a pharmaceutically acceptable salt or prodrug thereoffor treating, improving, or preventing motor complications associatedwith levodopa therapy for Parkinson's disease, wherein the tandospironeor a pharmaceutically acceptable salt or prodrug thereof is parenterallyadministered.

-   [Item 2C]

The tandospirone or a pharmaceutically acceptable salt or prodrugthereof of any one of the preceding items, wherein the parenteraladministration is selected from transdermal administration, intradermaladministration, subcutaneous administration, intramuscularadministration, and a combination thereof.

-   [Item 3C]

The tandospirone or a pharmaceutically acceptable salt or prodrugthereof of any one of the preceding items, wherein the parenteraladministration has sustainability or is sustainably administered.

-   [Item 4C]

The tandospirone or a pharmaceutically acceptable salt or prodrugthereof of any one of the preceding items, wherein the parenteraladministration comprises transdermal administration.

-   [Item 5C]

The tandospirone or a pharmaceutically acceptable salt or prodrugthereof of any one of the preceding items, wherein the motorcomplications comprise levodopa induced dyskinesia (PD-LID).

-   [Item 6C]

Tandospirone or a pharmaceutically acceptable salt or prodrug thereoffor treating, improving, or preventing motor complications associatedwith levodopa therapy for Parkinson's disease, wherein levodopa induceddyskinesia (PD-LID) is improved without resulting in a rebound symptom,and wherein the tandospirone or a pharmaceutically acceptable salt orprodrug thereof is transdermally administered.

-   [Item 7C]

The tandospirone or a pharmaceutically acceptable salt or prodrugthereof of any one of the preceding items, wherein levodopa induceddyskinesia (PD-LID) comprises peak-dose dyskinesia, diphasic dyskinesia,and a combination thereof.

-   [Item 8C]

The tandospirone or a pharmaceutically acceptable salt or prodrugthereof of any one of the preceding items, wherein the treatment,improvement, suppression of progression, or prevention of motorcomplications comprises improvement, suppression of progression, orprevention of a levodopa induced dyskinesia (PD-LID) symptom, reductionof a period of levodopa induced dyskinesia (PD-LID) manifestation, or acombination thereof.

-   [Item 9C]

Tandospirone or a pharmaceutically acceptable salt or prodrug thereoffor accomplishing the improvement, suppression of progression, orprevention of a levodopa induced dyskinesia (PD-LID) symptom, reductionof a period of levodopa induced dyskinesia (PD-LID) manifestation, or acombination thereof, wherein the tandospirone or a pharmaceuticallyacceptable salt or prodrug thereof is parenterally administered.

-   [Item 10C]

The tandospirone or a pharmaceutically acceptable salt or prodrugthereof of any one of the preceding items, wherein the improvement of alevodopa induced dyskinesia (PD-LID) symptom is a clinically significantimprovement or greater.

-   [Item 11C]

The tandospirone or a pharmaceutically acceptable salt or prodrugthereof of any one of the preceding items, wherein the improvement of alevodopa induced dyskinesia (PD-LID) symptom is to a sufficient level toattain a clinical effect.

-   [Item 12C]

The tandospirone or a pharmaceutically acceptable salt or prodrugthereof of any one of the preceding items, which is a transdermallyadministered formulation.

-   [Item 13C]

The tandospirone or a pharmaceutically acceptable salt or prodrugthereof of any one of the preceding items, which is an adhesiveformulation.

-   [Item 14C]

The tandospirone or a pharmaceutically acceptable salt or prodrugthereof of any one of the preceding items, wherein the transdermallyadministered formulation is a tape/patch.

-   [Item 15C]

The tandospirone or a pharmaceutically acceptable salt or prodrugthereof of any one of the preceding items, wherein a drug dosage of thetandospirone or a pharmaceutically acceptable salt or prodrug thereof is0.1 to 100 mg per day as a free form of tandospirone.

-   [Item 16C]

The tandospirone or a pharmaceutically acceptable salt or prodrugthereof of any one of the preceding items, wherein an amount of drugpenetration for the tandospirone or a pharmaceutically acceptable saltor prodrug thereof is 0.1 to 20 mg per day as a free form oftandospirone.

-   [Item 17C]

The tandospirone or a pharmaceutically acceptable salt or prodrugthereof of any one of the preceding items, wherein the tandospirone or apharmaceutically acceptable salt or prodrug thereof is a transdermallyadministered formulation, and a total applied area per dose is 1 to 100cm².

-   [Item 18C]

The tandospirone or a pharmaceutically acceptable salt or prodrugthereof of any one of the preceding items, wherein the tandospirone or apharmaceutically acceptable salt or prodrug thereof is administered sothat a human blood (plasma) tandospirone concentration is 0.05 to 20ng/mL for 12 hours or longer per day.

-   [Item 19C]

The tandospirone or a pharmaceutically acceptable salt or prodrugthereof of any one of the preceding items, wherein the tandospirone or apharmaceutically acceptable salt or prodrug thereof is administered sothat a human blood (plasma) tandospirone concentration is 0.05 to 20ng/mL for 8 to 16 hours after administration of the tandospirone or apharmaceutically acceptable salt or prodrug thereof.

-   [Item 20C]

The tandospirone or a pharmaceutically acceptable salt or prodrugthereof of any one of the preceding items, wherein the tandospirone or apharmaceutically acceptable salt or prodrug thereof is an adjunct oflevodopa.

-   [Item 21C]

The tandospirone or a pharmaceutically acceptable salt or prodrugthereof of any one of the preceding items, which is used with levodopaas the fixed-dose combination or concomitantly as separate formulations.

-   [Item 22C]

A combination of tandospirone or a pharmaceutically acceptable salt orprodrug thereof and (1) levodopa or (2) levodopa and a metabolizingenzyme inhibitor of levodopa for treating or preventing Parkinson'sdisease without accompanying or by minimizing PD-LID, wherein thetandospirone or a pharmaceutically acceptable salt or prodrug thereof isparenterally administered.

-   [Item 23C]

Tandospirone or a pharmaceutically acceptable salt or prodrug thereoffor treating or preventing Parkinson's disease without accompanying orby minimizing PD-LID, wherein the tandospirone or a pharmaceuticallyacceptable salt or prodrug thereof is administered in combination with(1) levodopa or (2) levodopa and a metabolizing enzyme inhibitor oflevodopa, wherein the tandospirone or a pharmaceutically acceptable saltor prodrug thereof is parenterally administered.

-   [Item 24C]

A combination of (1) levodopa or (2) levodopa and a metabolizing enzymeinhibitor of levodopa for treating or preventing Parkinson's diseasewithout accompanying or by minimizing PD-LID, wherein the combination of(1) levodopa or (2) levodopa and a metabolizing enzyme inhibitor oflevodopa is administered in combination with tandospirone or apharmaceutically acceptable salt or prodrug thereof, and wherein thetandospirone or a pharmaceutically acceptable salt or prodrug thereof isparenterally administered.

-   [Item 25C]

Tandospirone or a pharmaceutically acceptable salt or prodrug thereoffor improving the exacerbation in quality of response to levodopatherapy of a Parkinson's disease patient with dyskinesia, wherein thetandospirone or a pharmaceutically acceptable salt or prodrug thereof isparenterally administered.

-   [Item 26C]

The tandospirone or a pharmaceutically acceptable salt or prodrugthereof of any one of the preceding items, which is a free form.

In a specific embodiment, the present invention is provided as anadhesive formulation (also referred to as a transdermal patch/tapeagent). When the tape agent of the invention is applied, dyskinesiasymptoms associated with levodopa therapy for Parkinson's disease can bemore preferably prevented or improved. Therapy of Parkinson's diseasewherein a single dose and/or a daily dose of levodopa is increased,relative to prior to therapy using the tape agent of the invention,without exacerbation of dyskinesia, can be administered in an actualclinical setting when the tape agent of the invention is applied to morepreferably prevent or improve dyskinesia symptoms associated withlevodopa therapy for Parkinson's disease.

Current therapy attempts to treat Parkinson's disease patients withsmall and frequent doses of levodopa to prevent the manifestation ofdyskinesia (Pakinsonbyo Shinryo Gaidorain 2018 bajon [Parkinson'sDisease Diagnosis and Treatment Guidelines 2018 version] (Third edition,Q&A for Parkinson's disease diagnosis, Chapter III, Therapy for motorsymptoms)).

The manifestation of dyskinesia can be suppressed and the levodopacontaining formulation can be adjusted to an optimal dose byadministering a parenterally administered formulation of tandospironeprovided by the invention. In other words, a more preferred therapy ofParkinson's disease symptoms is enabled without exacerbating dyskinesiasymptoms, even if a single dose of levodopa is increased to reduce thenumber of doses or the daily dosage of levodopa is increased forParkinson's disease patients with or at a risk of manifestation ofdyskinesia.

The tandospirone or a pharmaceutically accepted salt or prodrug thereofand therapeutic method of the invention enable therapy or prevention toreduce levodopa induced motor complications or levodopa induceddyskinesia involving the normal daily dosage for levodopa therapyspecified in Pakinsonbyo Shinryo Gaidorain 2018 bajon [Parkinson'sDisease Diagnosis and Treatment Guidelines 2018 version] published bythe Japanese Society of Neurology or a corresponding guideline in the USor Europe.

Further, a more preferred effect of improving levodopa induceddyskinesia (PD-LID) or the like can be provided relative to oraladministration by administering a parenterally administered formulationof tandospirone provided by the invention.

The inventors have found for the first time that oral administration oftandospirone with expectation of an effect of improving dyskinesiainstead leads to temporary exacerbation of dyskinesia. In other words,the inventors have found that oral administration of tandospirone is notpreferable as a therapeutic drug for the improvement of dyskinesiabecause the oral administration involves a “rebound symptom” ofdyskinesia. As used herein, “rebound symptom” is the symptom describedin [0036]. Since oral administration of tandospirone results in a“rebound symptom”, it is not preferable to increase the dosage of alevodopa containing formulation.

The inventors have found that the tandospirone parenteral composition ofthe invention can improve dyskinesia without a “rebound symptom”. Adyskinesia score can be measured as an “AIMs score” (AIMs is anabbreviation for “abnormal involuntary movements”) by the methoddescribed in [0038].

Therefore, the present invention can be practiced as the followingspecific embodiments.

-   (1) A method of preventing or treating Parkinson's disease, a method    of improving dyskinesia, or a method of preventing or treating    Parkinson's disease with improved dyskinesia, comprising:-   (A) parenterally administering tandospirone; and-   (B) administering an increased dosage of levodopa compared to a    conventional dosage.-   (2) A method of preventing or treating Parkinson's disease, a method    of improving dyskinesia, or a method of preventing or treating    Parkinson's disease with improved dyskinesia, comprising:-   (A) parenterally administering tandospirone; and-   (B) increasing the dosage of levodopa to more than a conventional    single dosage to adjust the number of daily dosages.-   (3) A method of preventing or treating Parkinson's disease, a method    of improving dyskinesia, or a method of preventing or treating    Parkinson's disease with improved dyskinesia in a patient with or at    a risk of manifestation of dyskinesia, comprising:-   (A) parenterally administering tandospirone; and-   (B) administering levodopa with a maintained or increased dosage.-   (4) A method of preventing or treating Parkinson's disease, a method    of improving dyskinesia, or a method of preventing or treating    Parkinson's disease with improved dyskinesia in a patient with or at    a risk of manifestation of dyskinesia, comprising:-   (A) adding parenteral administration of tandospirone to conventional    levodopa therapy; and-   (B) increasing a levodopa dosage to the extent that dyskinesia is    not exacerbated and concomitantly using parenteral administration of    tandospirone.-   (5) A method of preventing or treating Parkinson's disease, a method    of improving dyskinesia, or a method of preventing or treating    Parkinson's disease with improved dyskinesia comprising:-   (A) maintaining a plasma concentration of tandospirone to 0.05 to 20    ng/mL; and-   (B) administering levodopa.-   (6) A method of preventing or treating Parkinson's disease, a method    of improving dyskinesia, or a method of preventing or treating    Parkinson's disease with improved dyskinesia in a patient with or at    a risk of manifestation of dyskinesia, comprising:-   (A) maintaining a plasma concentration of tandospirone to 0.05 to 20    ng/mL; and-   (B) administering levodopa.

The basis of the invention is the following.

*Since levodopa has a short half-life and the effect is not sustained,levodopa is generally administered multiple times per day. Meanwhile,the blood concentration of tandospirone is maintained for 24 hours whenthe tandospirone of the invention is administered as a tape agent, i.e.,applied one sheet per day. For this reason, for transdermallyadministered formulations, levodopa is administered while being exposedto tandospirone no matter at what time levodopa is administered. On theother hand, if a Sediel tablet and levodopa are administered (orallyadministered) at the same timing three times a day, levodopa would beadministered while the blood concentration of tandospirone is reduced.In other words, the feature is in being different from an oral agent.Further, it is preferable that the blood concentration of tandospironeis maintained upon administration of levodopa.

In a specific embodiment, the present invention can be used in variousapplications (indications). For example, indications such as improvementof dyskinesia (anti-dyskinesia drug) <PD-LID improving drug>, treatingdyskinesia (involuntary movements) in Parkinson's disease patientstreated with levodopa therapy, with or without other medicines thatincrease the effects of dopamine in the brain, a caution for use or alabel (package insert) can be appended.

The present invention is intended so that one or more of theaforementioned features can be provided not only as the explicitlydisclosed combinations, but also as other combinations. Additionalembodiments and advantages of the present invention are recognized bythose skilled in the art by reading and understanding the followingdetailed description, as needed.

As used herein, motor complications and dyskinesia refer to symptomsassociated with levodopa therapy for Parkinson's disease, and excludesymptoms originating from other diseases and symptoms associated withtherapy using a compound other than levodopa, unless specifically notedotherwise.

Advantageous Effects of Invention

The pharmaceutical composition of the invention has expectation as atherapeutic drug, improving drug, progression suppressing drug, orprophylactic drug for levodopa induced motor complications inParkinson's disease (e.g., levodopa induced dyskinesia (PD-LID), or thelike). Specifically, the pharmaceutical composition of the invention hasexpectation as a therapeutic drug, improving drug, progressionsuppressing drug, or prophylactic drug for PD-LID without a reboundsymptom.

BRIEF DESCRIPTION OF DRAWINGS

FIG. 1 is a diagram showing changes in plasma concentration when atandospirone tape agent was applied to a normal rat. Specifically,changes in plasma tandospirone concentrations obtained by applying atandospirone tape agent to a normal rat (9 cm²: 31±2 cm²/kg) are shownin terms of mean value±standard deviation. The x axis indicates the timefrom application, and the y axis indicates the plasma tandospironeconcentration.

FIG. 2 is a diagram showing results of evaluating dyskinesia-likesymptoms when a tandospirone tape agent was applied to a PD-LID ratmodel under administration condition 1. Specifically, a tandospironetape agent was transdermally administered to a PD-LID rat model andlevodopa was administered 4 hours later to evaluate dyskinesia-likesymptoms. The results are indicated in terms of mean value±standarderror. ** indicates p<0.01, meaning that there is a significantdifference compared to a placebo tape agent application group (Wilcoxonrank sum test). In the figure, graph A shows the changes in AIMs scoreover time after levodopa administration. Graph B shows the total AIMsscore in 180 minutes. Graph C shows the total AIMs score in 100 to 180minutes.

FIG. 3 is a diagram showing the results of evaluating dyskinesia-likesymptoms when a tandospirone tape agent was applied to a PD-LID ratmodel under administration condition 2. Specifically, a tandospironetape agent was transdermally administered to a PD-LID rat model on whichstratum corneum stripping was performed on the tape agent applicationsite, and levodopa was administered 4 hours later to evaluatedyskinesia-like symptoms. The results are indicated in terms of meanvalue±standard error. ** indicates p<0.01, meaning that there is asignificant difference compared to a placebo tape agent applicationgroup (Wilcoxon rank sum test). In the figure, graph A shows the changesin AIMs score over time after levodopa administration. Graph B shows thetotal AIMs score in 180 minutes. Graph C shows the total AIMs score in100 to 180 minutes.

FIG. 4 is a diagram showing results of evaluating dyskinesia symptomsupon continuous subcutaneous infusion of tandospirone to a PD-LID ratmodel. Specifically, tandospirone was subcutaneously and sustainablyadministered to a PD-LID rat model, and levodopa was administered 4hours later to evaluate the dyskinesia-like symptoms. The results areindicated in terms of mean value±standard error. * indicates p<0.05,meaning that there is a significant difference compared to the solventadministration group (Steel test). In the figure, graph A shows changesin the AIMs score over time after levodopa administration. Graph B showsthe total AIMs score in 180 minutes. Graph C shows the total AIMs scorein 100 to 180 minutes.

FIG. 5 is a diagram showing results of long term evaluation ofdyskinesia-like symptoms upon continuous subcutaneous infusion oftandospirone citrate to a PD-LID rat model. Specifically, tandospironecitrate was subcutaneously and sustainably administered to a PD-LID ratmodel, and dyskinesia-like symptoms were evaluated on the day ofstarting the administration and on day 13 of administration. The totalAIMs score in 180 minutes is indicated in terms of mean value±standarderror. ** indicates p<0.01, meaning that there is a significantdifference compared to a solvent administration group (Wilcoxon rank sumtest). In the figure, Graph A shows results on day 0 of implanting apump. Graph B shows results on day 13 of implanting a pump.

FIG. 6 is a diagram showing the effect of continuous subcutaneousinfusion of tandospirone citrate to rats treated on one side of thebrain with 6-hydroxydopamine on dyskinesia development. Specifically,levodopa was repeatedly administered and tandospirone citrate wassubcutaneously and sustainably administered to rats treated on one sideof the brain with 6-hydroxydopamine to evaluate the effect on levodoparepeated administration induced dyskinesia-like symptom manifestation.The results are indicated in terms of mean value±standard error. *indicates p<0.05, and ** indicates p<0.01, meaning that there is asignificant difference compared to the solvent administration group(Steel test). In the figure, graph A shows the results of levodoparepeated administration over time, and graph B shows results on the dayafter the completion of tandospirone citrate administration (day 16).

FIG. 7 is a diagram showing results of evaluating dyskinesia-likesymptoms when tandospirone citrate was orally administered to a PD-LIDrat model. Specifically, tandospirone citrate (10 mg/kg, 30 mg/kg ascitrate concentration) was orally administered to a PD-LID rat model,and levodopa was administered 5 minutes later to evaluatedyskinesia-like symptoms. The results are indicated in terms of meanvalue±standard error. * indicates p<0.05, meaning that there is asignificant difference compared to a solvent administration group (Steeltest). In the figure, graph A shows changes in AIMs score over timeafter levodopa administration. Graph B shows the total AIMs score in 180minutes. Graph C shows the total AIMs score in 100 to 180 minutes.

FIG. 8 shows results of evaluating dyskinesia-like symptoms whentandospirone citrate was orally administered to a PD-LID rat model.Specifically, tandospirone citrate (30 mg/kg, 100 mg/kg as citrateconcentration) was orally administered to a PD-LID rat model, andlevodopa was administered 5 minutes later to evaluate dyskinesia-likesymptoms. The results are indicated in terms of mean value±standarderror. In the figure, graph A shows changes in AIMs score over timeafter levodopa administration. Graph B shows the total AIMs score in 180minutes. Graph C shows the total AIMs score in 100 to 180 minutes.

FIG. 9 is a diagram showing X-ray powder diffraction patterns oftandospirone free form, tandospirone citrate (hydrate), and tandospironecitrate (anhydrate).

FIG. 10 shows results of evaluating dyskinesia-like symptoms when 1-PPdihydrochloride was subcutaneously administered to PD-LID rat models.Specifically, 1-PP dihydrochloride (10 mg/kg, 30 mg/kg) wassubcutaneously administered to PD-LID rat models, and levodopa wasadministered 5 minutes later to evaluate dyskinesia-like symptoms.Results are indicated in terms of mean value±standard error. In thefigure, graph A shows changes in AIMs score over time after levodopaadministration. Graph B shows the total AIMs score in 180 minutes. GraphC shows the total AIMs score in 100 to 180 minutes.

DESCRIPTION OF EMBODIMENTS

The present invention is explained hereinafter while showing the bestmodes thereof. Throughout the entire specification, a singularexpression should be understood as encompassing the concept thereof inthe plural form, unless specifically noted otherwise. Thus, singulararticles (e.g., “a”, “an”, “the”, and the like in the case of English)should also be understood as encompassing the concept thereof in theplural form, unless specifically noted otherwise. Further, the termsused herein should be understood as being used in the meaning that iscommonly used in the art, unless specifically noted otherwise.Therefore, unless defined otherwise, all terminologies and scientifictechnical terms that are used herein have the same meaning as thegeneral understanding of those skilled in the art to which the presentinvention pertains. In case of a contradiction, the presentspecification (including the definitions) takes precedence.

(Definitions, etc.)

The definitions and/or the basic technology of the terms that areespecially used herein are described hereinafter as appropriate.

As used herein, “tandospirone” [Chemical name:(1R,2S,3R,4S)-N-[4-{4-(pyrimidine-2-yl)piperadine-1-yl}butyl]-2,3-bicyclo[2.2.1]heptanedicarboximide]has the following structure.

A Sediel tablet comprising a citric acid salt of tandospirone as anactive ingredient is used for therapy as a serotonergic anxiolytic drug(e.g., Sediel package insert or label, revised in April 2016, 14thedition, Sumitomo Dainippon Pharma Co., Ltd.; see Japanese Laid-OpenPublication No. 58-126865). Tandospirone has a beneficial effect onmemory in chronic schizophrenia. In particular, it is known thatcognitive dysfunction can be improved by administering tandospirone or apharmaceutically acceptable salt thereof while continuing maintenancetherapy using a typical antipsychotic such as haloperidol (see JapaneseLaid-Open Publication No. 2002-20291).

As an active ingredient used in the pharmaceutical composition of theinvention, tandospirone (free form) is preferred, but a pharmaceuticallyacceptable salt of tandospirone or a prodrug of tandospirone can also beused in the same manner. Pharmaceutically acceptable salts and prodrugsof tandospirone include salts of inorganic acid such as hydrochloride,hydrobromide, sulfate, and phosphate and salts of organic acid such asacetate, butyrate, tartrate, citrate, maleate, and fumarate.

Prodrugs of tandospirone refer to any component, which has a differentstructure from tandospirone, but can be converted into tandospirone oran active ingredient based thereon by metabolism after administration toexert efficacy.

Prodrugs of tandospirone refer to compounds that are converted totandospirone due to a reaction with an enzyme, or the like underphysiological conditions in the body, i.e., compounds that are changedinto tandospirone as a result of enzymatic oxidation, reduction,hydrolysis, or the like. Prodrugs of tandospirone may also be compoundsthat are changed into tandospirone under physiological conditions suchas those described in “Iyakuhin no Kaihatsu” [Drug Development],Hirokawa-Shoten Ltd., 1990, Vol. 7, Molecular Design, pp. 163 to 198.

The tandospirone of the invention or a salt or prodrug thereof(hereinafter, also referred to as tandospirones) has excellent serotonin5-HT1A receptor activation action.

The tandospirone of the invention has low toxicity and is safe.

A drug with an active ingredient of “tandospirone citrate” is clinicallyapplied as an oral agent as a therapeutic agent for (1) depression orpanic in neurosis and (2) physical symptoms, and depression, anxiety,restlessness, or sleep disorder in a psychosomatic disease. Tandospironeis highly selective to serotonin 1A receptors (hereinafter, alsoreferred to as “5-HT1A receptor”), but has low affinity to dopamine 2receptors (also referred to as “D2 receptor”) in in vitro receptorbinding evaluation for various neurotransmitter receptors. For thisreason, tandospirone is understood as activating a 5-HT1A receptor andselectively acting on serotonin nerves to exert an effect on neurosis orthe like.

As used herein, “levodopa” (as broadly defined) includes the narrowlydefined levodopa (L-3,4-dihydroxyphenylalanine (IUPAC nomenclature is(S)-2-amino-3-(3,4-dihydroxyphenyl)propanoic acid); also called L-dopa)as well as any other drugs attaining the same efficacy asL-3,4-dihydroxyphenylalanine. Examples of such other drugs include, butare not limited to, esters of L-3,4-dihydroxyphenylalanine and saltsthereof. Examples of esters of L-3,4-dihydroxyphenylalanine includelevodopa ethyl ester (LDEE;ethyl(2S)-2-amino-3-(3,4-dihydroxyphenyl)propanoate), levodopa propylester; levodopa propyl ester(propyl(2S)-2-amino-3-(3,4-dihydroxyphenyl)propanoate), levodopa methylester (methyl(2S)-2-amino-3-(3,4-dihydroxyphenyl)propanoate), and thelike. An ester of L-3,4-dihydroxyphenylalanine can be, for example, asalt including hydrated salt. A salt of levodopa ester can include, butis not limited to, one of octanoate, myristate, succinate, succinatedihydrate, fumarate, fumarate dihydrate, mesylate, tartrate, andhydrochloride. Examples of succinate dehydrate or succinate of ester ofL-3,4-dihydroxyphenylalanine include levodopa ethyl ester succinate(LDEE-S) and levodopa ethyl ester succinate dehydrate (LDEE-S-dihydrateor LDEE-S(d))>

As used herein, “metabolizing enzyme inhibitor of levodopa” refers toany drug having action to inhibit the metabolism of broadly definedlevodopa to enhance the action thereof. Examples thereof include dopadecarboxylase inhibitors (DCI) that prevent levodopa from changing intodopamine in the intestine, liver, or blood vessel (examples thereofinclude carbidopa, α-methyldopa, benserazide (Ro4-4602),α-difluoromethyl-DOPA (DFMD), salts thereof, and the like),catechol-O-methyl transferase inhibitors (COMT-I) that similarly preventthe decomposition of levodopa before entering the brain (examplesthereof include entacapone), monoamine oxidase inhibitors (MAO-I) thatprevent the decomposition of dopamine in the brain (examples thereofinclude selegiline), and the like.

(Disease/Disorder)

As used herein, “motor complications” refer to any motor symptom that isa problem to be treated found in patients with advanced Parkinson'sdisease. Examples thereof include dyskinesia (levodopa induceddyskinesia (PD-LID)), which is an involuntary movement associated withlevodopa therapy, and the like. Motor complications are understood to bebased on excessive action of levodopa, but the mechanism thereof is notnecessarily elucidated.

As used herein, “levodopa induced dyskinesia <involuntary movement>(PD-LID)” refers to involuntary movement of the hand, leg, or bodyunintentionally weaving, which is induced by levodopa overdose. It isknown that dyskinesia is readily manifested if a large amount oflevodopa is continuously dosed more than necessary from the initialphase of the disease, and it is very difficult to control once it ismanifested, even if the dosage of levodopa is subsequently increased ordecreased to various levels. Peak-dose dyskinesia is known as anexemplary symptom of PD-LID. The symptom is manifested on the face,tongue, neck, limbs, body trunk, or the like when the blood levodopaconcentration is high.

Involuntary movement (dyskinesia) refers to a portion of the body movinginvoluntarily or not stopping, biting of the lips, difficulty in speech,inability to stay still, or difficulty in moving the hand or leg asintended, and is a motor disorder in which involuntary movement isobserved in the limbs and/or mouth or face, and/or body axis. Dyskinesiaobserved in PD patients undergoing therapy with levodopa is known aslevodopa induced dyskinesia (LID), which occurs in more than half of PDpatients who have had therapy with levodopa for the past 5 to 10 years.The percentage (%) of patients suffering from LID increases with passageof time (for an overview, see, for example, Encarnacion and Hauser,(2008), “Levodopa-induced dyskinesias in Parkinson's disease: etiology,impact on quality of life, and treatments.”, Eur Neurol, 60(2), pages 57to 66).

Peak-dose dyskinesia is involuntary movement resulting from excessiveantiparkinsonian drug. Diphasic dyskinesia is dyskinesia manifested intwo phases, i.e., at the start and near the end of the effect of anantiparkinsonian drug.

As used herein, “pharmaceutically acceptable salt” includes acid and/orbase salts formed with inorganic and/or organic acid and base. Examplesthereof include acid addition salts and base addition salts. Examples ofacid addition salts include inorganic acid salts such as hydrochloride,hydrobromide, sulfate, hydroiodide, nitrate, and phosphate, and organicacid salts such as citrate, oxalate, phthalate, fumarate, maleate,succinate, malate, acetate, formate, propionate, benzoate,trifluoroacetate, methanesulfonate, benzenesulfonate,p-toluenesulfonate, and camphorsulfonate. Examples of base additionsalts include inorganic base salts such as sodium salt, potassium salt,calcium salt, magnesium salt, barium salt, and aluminum salt, andorganic base salts such as trimethylamine, triethylamine, pyridine,picoline, 2,6-lutidine, ethanolamine, diethanolamine, triethanolamine,tromethamine [tris(hydroxymethyl)methylamine], tert-butylamine,cyclohexylamine, dicyclohexylamine, and N-N-dibenzylethylamine.Furthermore, examples of “pharmaceutically acceptable salt” includeamino acid salts of a basic or acidic amino acid such as arginine,lysine, ornithine, aspartic acid, and glutamic acid. Pharmaceuticallyacceptable salts are well known in the art. For example, Berge et al.describes pharmaceutically acceptable salts in detail in J.Pharmaceutical Sciences (1977) 66: 1-19.

The tandospirone or a pharmaceutically acceptable salt or prodrugthereof or medicament of the invention can comprise a carrier as needed.As used herein, the term “carrier” refers to a pharmaceuticallyacceptable substance, composition, or excipient such as a liquid orsolid bulking agent, diluent, additive, solvent, base agent, or skinpermeation promoting agent, which is associated with or enables thetransport or carriage of a target pharmaceutical compound from anorgan/tissue of the body or a part thereof to another organ/tissue ofthe body or a part thereof. “Pharmaceutically acceptable” refers tobeing compatible with other raw materials in the formulation and beingharmless to the subject.

Diseases that are treatable in the present invention include anylevodopa induced motor complication in Parkinson's disease.

In a specific embodiment, a patient who is treatable in the presentinvention includes Parkinson's disease patients who have or have thepotential of manifesting levodopa induced motor complications. Levodopainduced motor complications include levodopa induced dyskinesia.

The effect of improvement on levodopa induced dyskinesia in Parkinson'sdisease in the present invention can be clinically confirmed using apatient diary or a clinical evaluation scale such as Unified DyskinesiaRating Scale (UDysRS), Clinical Dyskinesia Rating Scale (CDRS), orAbnormal Involuntary Movement Scale (AIMS). The effect of improvingdyskinesia can also be confirmed by dyskinesia-like abnormal involuntarymovement behavior evaluation in a non-clinical model PD-LID rat model.The improvement, suppression of progression, or prevention of levodopainduced dyskinesia (PD-LID) symptoms, as well as reduction in the periodof levodopa induced dyskinesia (PD-LID) manifestation can be measured byusing this approach.

The present invention can confirm whether a PD-LID symptom isexacerbated by whether a clinical evaluation scale of dyskinesia such asUDysRS, CDRS, or AIMS has significantly deteriorated relative to beforetherapy with tandospirone. This can also be confirmed by whether clearexacerbation in a dyskinesia associated symptom is observed from apatient diary. Whether a levodopa induced dyskinesia symptom isaccompanied with pain can be confirmed herein with clinical records suchas a patient diary.

In the present invention, “rebound symptom” of levodopa induceddyskinesia (PD-LID) refers to a phenomenon in which the dyskinesia scoreis rather exacerbated temporarily by a therapeutic drug for improvingdyskinesia. A “rebound symptom” is a phenomenon with more exacerbationin dyskinesia than a case without therapy using a dyskinesia improvingdrug after the peak period (e.g., 1 hour) of antiparkinsonian action oflevodopa during therapy using the dyskinesia improving drug. The symptomis anticipated to manifest in 1 to 6 hours after administration oflevodopa.

In the present invention, improvement in levodopa induced dyskinesia(PD-LID) without a rebound symptom means that the total score fordyskinesia is improved without exacerbation of dyskinesia, not eventemporarily, compared to a case without therapy using a dyskinesiaimproving drug after levodopa administration. “Without exacerbation ofdyskinesia” refers to a condition with dyskinesia (AIMs score of 2 orgreater in an AIMs evaluation system of non-clinical PD-LID rat model)and without significant deterioration in the dyskinesia score comparedto a case without therapy using a dyskinesia improving drug.

A rebound symptom of levodopa induced dyskinesia (PD-LID) can beevaluated with clear dyskinesia-like symptoms (AIMs score of 2 orgreater) observed at 120 to 140 minutes after levodopa administration,total AIMs score in 100 to 180 minutes, or the like as an indicator inan AIMs evaluation system of non-clinical PD-LID rat model. Improvementof dyskinesia can be evaluated by a total AIMs score in 180 minutesafter levodopa administration. In this AIMs evaluation system of aPD-LID rat model, an AIMs score of 2 or greater is diagnosed asdyskinesia, and a greater number means more severe dyskinesia. An AIMsscore of less than 2 is diagnosed as no dyskinesia.

The inventors have found that oral administration of tandospironeresults in a rebound symptom, so that it is unsuitable for therapy ofPD-LID. Meanwhile, the inventors have found that parenteraladministration of tandospirone as in the present invention improveslevodopa induced dyskinesia (PD-LID) without a rebound symptom. Thetherapeutic mode is preferably sustained parenteral administration oftandospirone or parenteral administration of a sustained releaseformulation, and more preferably transdermal administration oftandospirone.

As used herein, “adjunct” refers to a drug other than the drug with theprimary action. If levodopa is the primary agent, tandospirone and thelike is an adjunct in the present invention.

The daily dosage of the primary agent levodopa herein is the normal dosefor levodopa therapy specified in Pakinsonbyo Shinryo Gaidorain 2018bajon [Parkinson's Disease Diagnosis and Treatment Guidelines 2018version] or a corresponding guideline in the US or Europe. In general,the normal daily dose of levodopa is 50 to 1200 mg/day and preferably100 mg to 600 mg/day in concomitant use or as a combined agent with aperipheral dopa decarboxylase inhibitor (DCI). For example, SINEMET®(Carbidopa-Levodopa combination tablet) (New Drug Application (NDA)#017555) approved by the FDA is provided as a 1:4 ratio combinationtablet (25 mg Carbidopa-100 mg Levodopa) and 1:10 ratio combinationtablet (10 mg Carbidopa-100 mg Levodopa or 25 mg Carbidopa-250 mgLevodopa). The daily maintenance dose of SINEMET® is administered sothat Carbidopa would be 70 mg to 100 mg. SINEMET® is administered at themaximum daily dose of up to 200 mg as Carbidopa.

The tandospirone or a pharmaceutically acceptable salt or prodrugthereof or therapeutic method herein can enable therapy to reduce motorcomplications associated with administration of a normal dose inlevodopa therapy or prevention of motor complications.

The levodopa dosage can be appropriately adjusted by administering thetandospirone or a pharmaceutically acceptable salt or prodrug thereof ofthe invention. The dosage can be increased within the range of thesingle dosage and daily dosage specified in, for example, PakinsonbyoShinryo Gaidorain 2018 bajon [Parkinson's Disease Diagnosis andTreatment Guidelines 2018 version] published by the Japanese Society ofNeurology or a corresponding guideline in the US or Europe.

As used herein, “has sustainability” can be determined by those skilledin the art by utilizing known findings in the art while considering thedescriptions herein. Specifically, having sustainability can be definedas maintaining a blood drug concentration for an extended period of timeand exhibiting an effect of prolonged biological half-life. Examples ofcompositions having sustainability include various transdermallyadministered formulations described in [0051], various sustained releaseinjection agents described in [0089], various implanted agents describedin [0090], and the like. As used herein, “sustainably administered”refers to sustained administration of an active ingredient in thepresent invention from outside to inside the body, which can be achievedthrough transdermal absorption, injection, infusion, or the like whileselecting a parenteral route of administration described in [0048].

As used herein, “clinically significant period” can be determined bythose skilled in the art by utilizing known findings in the art whileconsidering the descriptions herein. Specifically, if a significanteffect such as prevention, treatment, or alleviation of motorcomplications targeted by the present invention is exhibited, the periodof time can be defined as a clinically significant period. For“clinically significant improvement” as used herein, if a significanteffect such as prevention, treatment, or alleviation of motorcomplications targeted by the present invention is exhibited, the statecan be similarly defined as a clinically significant improvement. Theapproach to measure such a period or improvement can be appropriatelyselected by those skilled in the art. For example, any method describedherein can be considered. However, the method is not limited thereto.For example, Pakinsonbyo Shinryo Gaidorain 2018 bajon [Parkinson'sDisease Diagnosis and Treatment Guidelines 2018 version] published bythe Japanese Society of Neurology can also be used. Alternatively, it isreported that the dyskinesia clinical evaluation index (MDS UDysRS PartIII) is 2.32 points (Parkinsonism Relat Disord 21: 1349, 2015)). Themethod can be appropriately determined by considering (1) comparisonwith a placebo, (2) before and after therapy for each patient, or thelike.

As used herein, “sufficient period to attain a clinical effect” and“sufficient level to attain a clinical effect” can also be determined bythose skilled in the art by utilizing known findings in the art whileconsidering the descriptions herein. Specifically, if the period orlevel that can attain a clinical effect such as prevention, therapy, oralleviation of motor complications targeted by the present invention canbe measured, the period or level can be evaluated as a sufficient periodto attain a clinical effect. An approach of measuring such a period orlevel can be appropriately selected by those skilled in the art. Forexample, any method described herein can be considered. However, themethod is not limited thereto. For example, Pakinsonbyo ShinryoGaidorain 2018 bajon [Parkinson's Disease Diagnosis and TreatmentGuidelines 2018 version] published by the Japanese Society of Neurologyor a corresponding guideline in the US or Europe can also be used.

As used herein, “no” “exacerbation of a levodopa induced dyskinesia(PD-LID) symptom in a Parkinson's disease patient” means that an alreadydeveloped dyskinesia symptom is not exacerbated to a clinicallysignificant degree or is not significantly exacerbated, dyskinesiamanifestation period is not prolonged, a symptom is not significantlyexacerbated, not even temporarily, as in a rebound symptom ofdyskinesia, or a dyskinesia is not newly developed. A dyskinesia symptomcan be confirmed, for example, by measurement using UPDRS, UDysRS, CDRS,AIMS, or the like, or a clinical record such as a patient diary.

As used herein, “exacerbation in quality of response to levodopa therapyof a Parkinson's disease patient” refers to any decrease inresponsiveness of a patient to levodopa therapy. Such an exacerbation inthe quality of response can be measured from a dyskinesia symptom or thelike. “Improvement” of “exacerbation in quality of response to levodopatherapy of a Parkinson's disease patient” refers to improvement in thedegree of dyskinesia symptom in levodopa therapy of each patient. Theimprovement can be confirmed by measurement using UPDRS, UDysRS, CDRS,AIMS, or the like, or a clinical record such as a patient diary.

As used herein, “parenteral administration” refers to a dosage form forany route that is not oral administration. Preferably, any mode foradministering tandospirone in a mode and level that are effective forlevodopa induced motor complications in Parkinson's disease is employed.Examples of means of parenteral administration include administrationthrough transdermal absorption or transmucosal absorption, as well asinjection, infusion, and combinations thereof. For example,administration through transdermal absorption or transmucosal absorptionexerts an effect by contacting a transdermally administered formulationsuch as a paste agent, adhesive formulation, or spray to the skin ormucous membrane so that a drug in the formulation migrates into the bodythrough the skin or mucous membrane. Examples of administration viainjection or infusion include intravenous, intradermal, subcutaneous,intramuscular, and enteral administration (intestinal infusion), whichcan also be administered as a bolus and/or sustained infusion. Injectionor infusion can use a suspension, liquid agent, emulsion, or implantedagent in an oily or aqueous medium, comprising another formulationsubstance such as a suspending agent, stabilizer, and/or a dispersant.Enteral administration (intestinal infusion) can provide sustained drugdelivery to the proximal small intestine by using a tube or portableinfusion pump by percutaneous endoscopic gastrostomy. In a preferredembodiment, parenteral administration can be performed in a form of asustained administration. Such sustained administration can beaccomplished with transdermal patch/tape or the like, injection,infusion, or the like.

In the present invention, tandospirone or a pharmaceutically acceptablesalt or prodrug thereof is preferably administered by a method that canmaintain blood drug concentration for a long period of time, and is morepreferably administered by a method that can suppress the generation ofmetabolites. Examples of administration methods include transdermaladministration and injection such as subcutaneous, intradermal, andintramuscular administrations. Injection such as subcutaneous,intradermal, and intramuscular administrations is preferably a method ofadministration that sustains the blood concentration. In particular,transdermal administration is the most preferred because it is anadministration method that has a low degree of invasiveness and requiresno hospital visits.

In the present invention, treatment, improvement, suppression ofprogression, or prevention of motor complications associated withlevodopa therapy for Parkinson's disease by parenteral administrationincluding tandospirone or a pharmaceutically acceptable salt or prodrugthereof is preferred compared to therapy using an active ingredientother than the inventions herein or therapeutic methods and compositionsother than the inventions herein from the viewpoint of having no adverseeffect on levodopa action time (ON-time), having no adverse effect onparkinsonian symptoms (can be evaluated by UPDRS or the like), having noattenuation in the effect of the invention in repeated administration,capability to reduce the number of doses of levodopa formulations perday by increasing a levodopa formulation to the optimal dose withoutexacerbating motor complications, and the like.

“Transdermally administered formulation” refers to a paste agent,adhesive formulation, or spray (aerosol). Specific examples of adhesiveformulations include tape agents (transdermal patch), poultice, plaster,and the like, and examples of paste agents include ointment, cream,lotion, liniment, liquid agent, gel, and the like. A transdermallyadministered formulation is preferably an adhesive formulation and morepreferably a tape agent (transdermal patch). Since a “tape agent” issynonymous with a “patch” in the present invention, they are alsodenoted as “tape/patch” herein.

A transdermally administered formulation is manufactured by a knownmethod using a pharmaceutically acceptable additive. In one embodiment,a transdermally administered formulation used in the present inventionhas an adhesive layer provided on a support, and the adhesive layer canbe manufactured by including a thermoplastic elastomer or the like. A“thermoplastic elastomer” is an elastomer that softens and exhibitsfluidity when heated, and exhibits thermoplasticity of returning to arubber-like elastic when cooled. Examples thereof include variousthermoplastic elastomers such as urethane, acrylic, styrene, and olefinbased elastomers.

For the transdermally administered formulation of the invention, anadhesive layer can comprise nonvolatile hydrocarbon oil. As nonvolatilehydrocarbon oil, a chained saturated hydrocarbon with about 20 to 40carbons or chained unsaturated hydrocarbon with about 20 to 40 carbonsis preferable. Examples thereof include liquid paraffin, squalene,squalane, pristane, and the like. In particular, liquid paraffin is morepreferable from the viewpoint of availability. Liquid paraffin is amixture of colorless, odorless liquid alkanes with 20 or more carbons.In the present invention, liquid paraffin that is in compliance with thespecification specified in the Japanese Pharmacopoeia, US Pharmacopoeia,or the like can be preferably used. Nonvolatile hydrocarbon oil withhigh viscosity is preferred. Use of liquid paraffin with high viscosityis especially preferable from the viewpoint of adhesiveness.

An adhesive layer can also comprise a tackifier as needed. A tackifieris generally a resin that is commonly used for imparting skinadhesiveness in the art of adhesive formulations. Examples thereofinclude rosin based resin, polyterpene resin, coumarone-indene resin,petroleum-based resin, terpene-phenol resin, alicyclic saturatedhydrocarbon resin, and the like. One or more thereof can be selectedtherefrom and used.

If transdermal administration is envisioned, this can also bematerialized by applying an ointment to the skin

A dosage form for parenteral administration (e.g., transdermaladministration) of the tandospirone or a pharmaceutically acceptablesalt or prodrug thereof disclosed herein, other than a tape/patch, caninclude powder, spray, ointment, paste, cream, lotion, gel, and liquidsolution.

Ointment, paste, cream, and gel can comprise, in addition to thetandospirone or a pharmaceutically acceptable salt or prodrug thereofdisclosed herein, an additive such as animal and plant fat, oil, wax,paraffin, starch, tragacanth, cellulose derivative, polyethylene glycol,silicone, bentonite, silicic acid, talc, or zinc oxide, or a mixturethereof.

Powder and spray can comprise, in addition to the pharmaceuticalcomposition disclosed herein, an additive such as lactose, talc, silicicacid, aluminum hydroxide, calcium silicate, or polyamide powder or amixture thereof. A spray can further comprise a common high pressure gassuch as chlorofluorohydrocarbon or volatile unsubstituted hydrocarbonsuch as butane or propane.

In addition to ointment, powder, solution, and the like are alsounderstood to be within the scope of the disclosure herein, as long asit is suitable for parenteral administration.

A composition suitable for parenteral administration can comprise atleast one type of pharmaceutically acceptable aseptic isotonic aqueousor non-aqueous solution, dispersion, suspension, emulsion, implantedagent, or aseptic powder that can be reconstituted into an asepticinjection solution or dispersion immediately before use.

The composition disclosed herein can be prepared as a suppository forrectal or vaginal administration. The composition can be prepared bymixing one or more compounds according to the disclosure herein with oneor more suitable non-stimulatory additives or carriers including cocoabutter, polyethylene glycol, suppository wax, salicylate, or the like.The composition is a solid at room temperature, but is a liquid at bodytemperature. Thus, the composition melts in the rectum or the vaginalcavity to release the compound in the disclosure herein. Apharmaceutical composition suitable for vaginal administration caninclude a pessary, tampon, cream, gel, paste, foam, or spray formulationcomprising a carrier known to be suitable in prior art.

As used herein, “drug dosage” is the amount of drug contained in acomposition. As used herein, “amount of drug penetration” is the amountof drug intake into the body. If a composition is a transdermallyadministered formulation, “amount of drug penetration” is the amount ofdrug that has absorbed into the skin from the transdermally administeredformulation, and is a value calculated by the following equation.“Amount of residual drug” is the amount of drug remaining in thetransdermally administered formulation that has been peeled off afterapplication. This amount can be quantified by the method described inthe Examples (Reference Manufacturing Example) ([0098˜0101] or the like.Amount of drug penetration (mg/day)=drug dosage (mg/day)−amount ofresidual drug (mg/day)

In the present invention, the drug dosage, amount of drug penetration,amount of residual drug, and blood (plasma) tandospirone concentrationare amounts converted in terms of tandospirone free form, unlessspecifically noted otherwise.

In the present invention, the dosage or amount of penetration oftandospirone or a salt thereof can be appropriately adjusted dependingon the type of compound, symptom/age/body weight/kidney or liverfunction of the patient, or the like. For example, the daily drug dosageis 0.1 to 100 mg, and preferably 0.2 to 50 mg or the like. Examples ofthe upper limit thereof include 100 mg, 80 mg, 50 mg, 30 mg, 15 mg, andthe like. Examples of lower limit include 0.1 mg, 0.2 mg, 1 mg, 2 mg, 3mg, and the like. Examples of a preferred range include any combinationof these upper limits and lower limits. The daily amount of drugpenetration can be 0.1 to 20 mg, preferably 0.2 to 10 mg. Examples ofthe upper limit thereof include 20 mg, 10 mg, 8 mg, 7 mg, 5 mg, 3 mg,and the like. Examples of the lower limit include 0.1 mg, 0.2 mg, 1 mg,1.5 mg, and the like. Examples of a preferred range include anycombination of these upper limits and lower limits. The dosing frequencycan be appropriately adjusted depending on the property of thecomposition. If the composition is a transdermally administeredformulation, the frequency is for example once every 12 hours to onceevery 7 days. Any frequency therebetween can also be selected, such asonce every 2 days, once every 3 days, once every 4 days, or the like. Ifthe composition is an injection formulation, the frequency is, forexample, once daily to once every 3 months. Any frequency therebetweencan be selected, such as once a week, once every two weeks, once every 4weeks, once every 3 months, or the like. It is also possible to adjustthe dosing time depending on the symptom with a pump-style automaticinjector for sustained administration for 24 hours, or foradministration only when the patient is awake. The agent can be mixedwith a formulation comprising levodopa and sustainably administered.

In the present invention, tandospirone or a pharmaceutically acceptablesalt or prodrug thereof is preferably administered so that the humanblood (plasma) tandospirone concentration is 0.05 to 20 ng/mL as theamount converted in terms of a free form in a period during whichlevodopa is desired to be active. Specifically, the period is 12 hoursor longer, preferably 16 hours or longer per day.

Examples of the human blood (plasma) tandospirone concentration include0.05 to 20 ng/mL and the like as an amount converted in terms of freeform. Examples of the upper limit thereof include 20 ng/mL, 15 ng/mL, 10ng/mL, 8 ng/mL, 5 ng/mL, and the like. Examples of the lower limitinclude 0.05 ng/mL, 0.1 ng/mL, 0.2 ng/mL, 0.5 ng/mL, 1 ng/mL, and thelike. Examples of a preferred range include any combination of theseupper limits and lower limits. The aforementioned human blood (plasma)tandospirone concentration can be attained with a single administrationor as a maintenance concentration by repeated administration.

In the present invention, examples of the maximum value (Cmax) of humanblood (plasma) tandospirone concentration include 0.1 to 20 ng/mL andthe like as an amount converted in terms of free form. Examples of theupper limit thereof include 20 ng/mL, 15 ng/mL, 10 ng/mL, 8 ng/mL, 5ng/mL, and the like. Examples of the lower limit include 0.1 ng/mL, 0.2ng/mL, 0.5 ng/mL, 1 ng/mL, and the like. Examples of a preferred rangeinclude any combination of these upper limits and lower limits.

In the present invention, examples of the area under the human blood(plasma) tandospirone concentration-time curve (AUC) include 3 to 700ng·h/mL and the like as an amount converted in terms of free form.Examples of the upper limit thereof include 700 ng·h/mL, 600 ng·h/mL,400 ng·h/mL, 300 ng·h/mL, 200 ng·h/mL, and the like. Examples of thelower limit include 3 ng·h/mL, 5 ng·h/mL, 10 ng·h/mL, 30 ng·h/mL, andthe like. Examples of a preferred range include any combination of theseupper limits and lower limits.

In the present invention, a composition comprising tandospirone or apharmaceutically acceptable salt or prodrug thereof is a compositioncharacterized by being administered so that the human blood (plasma)tandospirone concentration is 0.05 to 20 ng/mL for 8 to 16 hours afteradministration of the tandospirone or a pharmaceutically acceptable saltor prodrug thereof.

In the present invention, if the composition comprising tandospirone ora pharmaceutically acceptable salt or prodrug thereof is a transdermallyadministered formulation, the formulation application area thereof cangenerally be adjusted when appropriate, but the total application areaper dose is preferably 1 to 100 cm². Examples of the upper limit thereofinclude 100 cm², 50 cm², 40 cm², 30 cm², 20 cm², and the like. Examplesof the lower limit include 1 cm², 2 cm², 4 cm², 9 cm², and the like.Examples of a preferred range include any combination of these upperlimits and lower limits, which enables a preferred therapeutic effect tobe attained.

The tandospirone or a pharmaceutically acceptable salt or prodrugthereof of the invention exceeds the lower limit value of the humanblood (plasma) tandospirone concentration within 8 hours, preferablywithin 6 hours, and more preferably within 4 hours after a single dose,and the human blood (plasma) tandospirone concentration is maintained inthe range between the upper limit and the lower limit for up to 16hours, preferably up to 18 hours, and more preferably up to 20 hoursafter the single dose.

In the present invention, a tandospirone transdermally administeredformulation is provided for therapy of Parkinson's disease byconcomitant use with a levodopa containing formulation. The tandospironetransdermally administered formulation in the present invention can beexpected to have a preferred effect by administration of a levodopacontaining formulation after 6 hours, preferably after 8 hours, and morepreferably after 12 hours from application of the tandospironetransdermally administered formulation. Further, a stable therapeuticeffect is attained without depending on the timing of administering alevodopa containing formulation by repeatedly administering atandospirone transdermally administered formulation by replacing theformulation every predetermined amount of time.

A manufacturing method of the transdermally administered formulation ofthe invention is described hereinafter, but the present invention is notlimited thereto.

The transdermally administered formulation of the invention can bemanufactured by a commonly known method. The tape agent of the inventioncan be manufactured, for example, according to the followingManufacturing Example 1.

MANUFACTURING EXAMPLE 1

A common manufacturing method of tape agents (transdermal patch) isdescribed.

The tape agent of the invention can be manufactured by a common method.For example, the tape agent can be manufactured in accordance with thesection directed to the manufacture of plaster agents described in“Keihi Tekiyo Seizai Kaihatsu Manyuaru” [Development manual fortransdermally applied formulation], supervised by Mitsuo Matsumoto(1985). The tape agent can also be manufactured, for example, by anapparatus, method, or the like described in “Development of PortableEquipment for Manufacturing Transdermal Patches (MEMBRANE), 32(2),116-119 (2007))”.

Specifically, a common manufacturing method of adhesive tape can beapplied for forming an adhesive layer in the manufacture of the tapeagent of the invention. A typical example thereof is a solvent coatingmethod, but hot melt coating method, electron beam curing emulsioncoating method, or the like can also be used.

To form an adhesive layer using the solvent coating method,tandospirone, adhesive containing mixture, penetration enhancer, curingagent, and other formulation components are mixed with an organicsolvent to prepare an adhesive layer mixture, and the mixture is appliedto one side of a support or a release liner and dried, then the organicsolvent is removed, and the release liner or support is pasted on beforeor after drying. The thickness of an adhesive layer of a tape agent isnot particularly limited, but is preferably about 10 μm to about 400 μm,more preferably about 20 μm to about 200 μm, still more preferably about50 μm to about 180 μm, and especially preferably about 70 μm to about150 μm.

MANUFACTURING EXAMPLE 2

Preparation of Other Parenterally Administered Formulations

An ointment can be manufactured by a commonly known method. An oil andfat ointment can generally be manufactured by heating and melting an oiland fat substrate of hydrocarbons or the like such as oil and fat, wax,or paraffin, adding an active ingredient, mixing to dissolve or dispersethe active ingredient, and mixing and kneading until the entire mixtureis homogeneous. A water soluble ointment can generally be manufacturedby heating and melting a water soluble substrate such as macrogol,adding an active ingredient, and mixing and kneading until the entiremixture is homogenous.

An ointment can be manufactured by blending tandospirone with higheralcohols such as cetanol or stearyl alcohol, higher fatty acid such asmyristic acid, lauric acid, palmitic acid, stearic acid, or linoleicacid or an ester thereof, wax such as purified lanolin or spermaceti,surfactant such as sorbitan fatty acid ester or sucrose fatty acidester, and hydrocarbons such as hydrophilic petrolatum, liquid paraffin,or plastibase. The composition of such an ointment formulation is, forexample, 0.5 to 10% by weight of tandospirone, 0.1 to 5% of higheralcohol, 1 to 15% by weight of higher fatty acid or ester thereof, 1 to10% by weight of surfactant, 4 to 10% by weight of wax, and 50 to 80% byweight of hydrocarbon. An ointment can be obtained, for example, by amanufacturing method comprising adding tandospirone and theaforementioned additive components and mixing the ingredients whileheating, and maintaining a temperature of 50 to 100° C., and once allthe ingredients become a transparent dissolved solution, mixing theingredients homogenously with a homogenizer mixer, and then stirringwhile cooling and allowing the mixture to cool.

An injection agent or formulation for subcutaneous, intradermal, orintramuscular administration can be manufactured by a commonly knownmethod. Such an injection agent can generally be manufactured by thefollowing method.

-   (i) An active ingredient is filled directly, or an active ingredient    with an addition of an additive is dissolved, suspended, or    emulsified into injection water, other aqueous or non-aqueous    solution or the like and homogenized, and the solution is filled    into an injection container, sealed, and sterilized.-   (ii) An active ingredient is filled directly, or an active    ingredient with an addition of an additive is dissolved, suspended,    or emulsified into injection water, other aqueous or non-aqueous    solution, or the like and homogenized, and the solution is    aseptically filtered or aseptically prepared and homogenized and    then filled into an injection container and sealed.

The injection agent can also be manufactured as a lyophilized injectionagent or powder injection agent to prevent degradation or inactivationof the active ingredient in a solution.

A lyophilized injection agent can generally be manufactured by fillingan active ingredient directly, or filling an active ingredient and anadditive such as an excipient, which are dissolved into injection waterand aseptically filtered, into a container for an injection agent andthen lyophilizing, or lyophilizing the ingredient in a specializedcontainer and then directly filling a container therewith.

A powder injection agent can generally be manufactured by filling acontainer for an injection agent with powder obtained by filtration withan aseptic filter and then crystallization or the powder with additionof a sterilized additive.

For example, an active ingredient solution is prepared by dissolvingtandospirone in water, organic solvent, or mixture of water and organicsolvent, together with a surfactant. The resulting solution can befiltered and sterilized with a sterilization filter to prepare anaseptic active ingredient solution. In this regard, the solvent used forthe dissolution (water, organic solvent, or mixture of water and organicsolvent) is preferably an organic solvent or a mixture of an organicsolvent and water, and more preferably a mixture of an organic solventand water. A sterilization filter is effective for filtration andsterilization, as well as removal of foreign objects originating fromraw materials or exogenous foreign objects mixed in during themanufacturing process.

Examples of surfactants include polysorbate 80, polysorbate 20,polyoxyethylene hydrogenated castor oil 50, polyoxyethylene hydrogenatedcastor oil 60, poloxamer 188, polyoxyethylene castor oil, benzalkoniumchloride, sodium lauryl sulfate, and the like, and two or more thereofcan also be used. A surfactant is preferably polysorbate 80. Asurfactant is preferably used at about 0.005% (w/v) to about 10% (w/v).As the water, purified water, water of the same or higher grade thanpurified water, or injection water is used. Examples of organic solventinclude alcohol solvents (e.g., methanol, ethanol, and the like),aprotic solvents (e.g., acetone, dimethyl sulfoxide,N,N-dimethylacetamide, and the like), and the like, or two or moresolvents can be used. The organic solvent is preferably 1-propanol,methanol, ethanol, 2-propanol, acetone, dimethyl sulfoxide, orN,N-dimethylacetamide.

The injection agent of the invention can be intramuscularly orsubcutaneously injected after attaching an injection needle to aprefilled syringe filled with a formulation. The injection agent canalso be administered by aspirating a formulation from a container suchas vial filled with the formulation into an injection syringe via aninjection needle and then discharging the formulation intramuscularly orsubcutaneously. Furthermore, a formulation can be a lyophilizedformulation obtained by filling the formulation into a container such asa vial and lyophilizing the formulation, or a powder filled formulationprepared by filling dried powder crystal obtained by isolating and thendrying the active ingredient crystal in the formulation in a containersuch as a vial. Lyophilized formulations and powder filled formulationscan be intramuscularly or subcutaneously injected after aspirating asuspension prepared by suspending the formulation in a container with asuspension solution at the time of use from the container into aninjection syringe via an injection needle. The injection agent of theinvention can also be intramuscularly or subcutaneously injected afterplacing a container filled with a formulation on a needleless syringe(syringe capable of administration without an injection needle byutilizing pressure generated by gas, initiating agent, spring, or thelike incorporated into an injection device, and having a mechanism fordischarging the drug solution filled in the container).

Example of Preparing a Sustained Injection Pump

The injection agent of the invention can be sustainably administered byusing a commercially available subcutaneous sustained injection pump. Asubcutaneous sustained injection pump is an apparatus for subcutaneouslyinjecting a drug sustainably to a patient via an injection tube, havinga drug storage unit and a pump for sustained injection of the drug. Suchan apparatus generally has a built-in clock and program that can changethe amount of injection per a certain period of time. A drug storageunit is a sealed container filled with a drug solution adjusted to adrug concentration required for the drug efficacy, comprising a druginlet and outlet for connection to the pump. A pump is a pump that cansustainably inject the drug solution precisely at a minute amount, whichis an apparatus that can injection a minute amount of liquid from about0.1 mL/day to 10 mL/hr. A drug storage unit is filled with and stores anaseptically guaranteed tandospirone solution.

A sustained injection agent is an injection agent that is appliedsubcutaneously, intradermally, intramuscularly, or the like in order torelease an active ingredient over a long period of time. A sustainedinjection agent can be manufactured by a commonly known method,generally by dissolving or suspending an active ingredient in plant oilor the like, or by preparing a suspension of microspheres usingbiodegradable macromolecular compounds.

An implanted agent is a solid or gel-like injection agent applied usingan instrument for implantation under the skin, in the muscle, or thelike, or by surgery in order to release an active ingredient over a longperiod of time. An implanted agent can be manufactured by a commonlyknown method. An implanted agent can generally be obtained by using abiodegradable macromolecular compound to prepare a pellet, microsphere,or gel-like formulation.

(Combined Drug)

The transdermally administered formulation of the invention can beconcomitantly used with an existing therapeutic agent for Parkinson'sdisease other than levodopa. Examples of such an existing therapeuticdrug for Parkinson's disease include, but are not limited to, dopamineagonists (e.g., bromocriptine, pergolide, talipexole, cabergoline,pramipexole, ropinirole, rotigotine, and the like), monoamine oxidase B(MAOB) inhibitors (e.g., selegiline, rasagiline, and Safinamide),catechol-O-methyltransferase (COMT) inhibitors (e.g., entacapone),amantadine, apomorphine, istradefylline, anticholinergic drugs (e.g.,biperiden, trihexyphenidyl, profenamine, and mazaticol), tiapride,droxidopa, carbidopa, zonisamide, and the like.

The present invention is specifically described in more detail withReference Examples, Examples, and Test Examples, but the presentinvention is not limited thereto. The compound names used in thefollowing Reference Examples, Examples, and the like do not necessarilyfollow the IUPAC nomenclature.

EXAMPLES

The Examples are described hereinafter.

While the products described in the Examples were used as the specificreagents, the products can be substituted with an equivalent productfrom other manufacturers (Sigma-Aldrich, Wako Pure Chemical, NacalaiTesque, R&D Systems, USCN Life Science INC, or the like).

Manufacturing Example Reference Manufacturing Example 1 Manufacture ofTandospirone

Tandospirone((1R,2S,3R,45)-N-[4-[4-(pyrimidine-2-yl)piperadine-1-yl]butyl]-2,3-bicyclo[2.2.1]heptanedicarboximide)has the chemical formula set forth below. The manufacturing methodthereof is described in Japanese Laid-Open Publication No. 58-126865.The description thereof is incorporated herein by reference.

Reference Manufacturing Example Manufacture of Tandospirone Tape Agent)

(Manufacture of Tandospirone Tape Agent)

An acrylic adhesive (MAS683, CosMED Pharmaceutical Co. Ltd., 35.6% byweight solids, 12.5068 g), ethyl acetate (1.5 mL), and polyoxyethylenelauryl ether (0.2530 g) were mixed. An ethyl acetate (5.5 mL) solutionof tandospirone (0.32512 g) was prepared and added to the mixture ofadhesive and thoroughly stirred. The resulting mixture was spread on asupport and dried for one day at room temperature. A release liner wasthen pasted therewith to manufacture a tandospirone tape agent.

(Manufacture of Placebo Tape Agent)

An acrylic adhesive (MAS683, CosMED Pharmaceutical Co. Ltd., 35.6% byweight solids, 18.6962 g), ethyl acetate (5.5 mL), and polyoxyethylenelauryl ether (0.3520 g) were mixed and thoroughly stirred. The resultingmixture was spread on a support and dried for one day at roomtemperature. A release liner was then pasted therewith to manufacture aplacebo tape agent.

50.8 μm of polyethylene terephthalate and/or ethylene vinyl acetatecopolymer laminate film (Scotchpak #9732) from 3M Health Care Ltd. wasused as the support. Bynasheet 64S-018B from Fujimori Kogyo Co., Ltd.was used as the release liner.

TABLE 1 Table. Drug content in tandospirone tape agent ThicknessTandospirone content (μm) (mg/cm²) Formulation 1 99 0.6 Formulation 2 940.6 Formulation 3 114 0.7 Formulation 4 105 0.7 Formulation 5 150 1.0

Measurement of Amounts of Drug (Drug Dosage) and Residual Drug in TapeAgent

While an example of measurement conditions for the drug dosage andamount of residual drug is described below, another measurement methodverified to be able to measure drug dosage or amount of residual drug oftandospirone can be used instead.

<Example of Measurement Conditions>

Preparation of Standard Solution

A tandospirone solution (about 4, 20, or 100 μg/mL) is prepared.

Preparation of Formulation Solution

-   (1) A tape agent is placed in a container. 10 mL of acetone is    added, and ultrasound wave is irradiated thereon for 30 minutes.-   (2) 1 mL of methanol is added to 1 mL extract of (1) and mixed.-   (3) The solution is filtered with a filter (Millipore: Millex-FH    (0.45 μm, PTFE)).

High Performance Liquid Chromatography (HPLC) Condition

-   Column: YMC-Pack ODS-AM 250×4.6 mm (particle size: 5 μm)-   Column oven: 40° C.-   Detector: ultraviolet absorption spectrophotometer (measurement    wavelength: 240 nm)-   Flow rate: 0.9 mL/min-   Amount injected: 10 μL-   Mobile phase: 10 mM phosphate buffer (pH 6.8)/acetonitrile mixture    (35:65)

(Evaluation of Plasma Concentration)

1. Testing Method

1.1. Pretreatment Operation Method

50 μL of rat plasma sample was fractionated into a polypropylenemicrotube. 50 μL of methanol (50 μL of standard solution for calibrationcurve sample) and 200 μL of internal standard solution (Bezafibratemethanol solution: 200 nmol/L, 200 μL of methanol for blank sample) areadded and stirred for about 10 seconds with a mixer. This is centrifuged(4° C., 4500 rpm, 10 min), and then the supernatant is subjected tovacuum filtration using a filter (FastRemover MF 0.2 μm). 70 μL ofaqueous 10 mmol/L ammonium acetate solution is added to 70 μL of theresulting filtrate and stirred for about 10 seconds with a mixer toprepare a measurement sample.

The tandospirone concentration is measured by liquid chromatography-massspectrometry.

1.2. Measurement Conditions

-   Column: XSELECT CSH C18, 3.5 μm, 100×3.0 mm I.D.-   Column temperature: 50° C.-   Mobile phase A: aqueous 10 mmol/L ammonium acetate solution-   Mobile phase B: methanol-   Flow rate: 0.6 mL/min-   Gradient condition:

TABLE 2 Time (min) 0 0.10 5.00 6.00 6.01 9.00 Mobile phase 15 15 95 9515 15 B(%)

-   Ionization method: electrospray ionization-   Detection method: multiple reaction monitoring, positive ion    detection mode-   Monitor ion: 384.2/122.1 (tandospirone Q1/Q3, m/z), 362.02/138.9    (Bezafibrate Q1/Q3, m/z)

Example 1 Evaluation of Changes in Plasma Concentration whenTandospirone Tape Agent is Applied to a Normal Rat

(Testing Method)

Wistar male rats (14-week old, Japan SLC, Inc.) were used. The abdominalregions of the rats were shaved prior to the tape agent evaluation date,and the tape agent of formula 1 was applied to the abdominal regions onthe evaluation date (the size was 9 cm²). Blood was collected over timeafter 2, 4, 6, and 24 hours from administration by the application toanalyze the plasma tandospirone concentration. The results are indicatedby mean value±standard deviation.

(Results)

Changes in the plasma tandospirone concentration shown in FIG. 1 wereobserved by applying a tandospirone tape agent (9 cm²: 31±2 cm²/kg). Itwas confirmed that the tape agent smoothed out and sustained the bloodconcentration of tandospirone.

Example 2 Evaluation of the Dyskinesia Improving Effect of TandospironeTape Agent

A rat striatum dopaminergic denervation model using topicaladministration of 6-hydroxydopamine (hereinafter, also referred to as“6-OHDA”) to one side of the brain is known as a typical experimentalmodel for PD-LID (rats treated on one side with 6-OHDA (6-OHDA-lesionedrats)). Dyskinesia-like abnormal involuntary movements (AIMs) manifestin said model with repeated administration of levodopa (Lundblad et al.,European Journal of Neuroscience, 2002, 15: 120-132, Winkler et al.,Neurobiology of Disease, 2002, 10: 165-186).

(Testing Method)

Wistar male rats (12-week old, Japan SLC, Inc.) were used for thepreparation of animal models. Desipramine hydrochloride (25 mg/kg; WakoPure Chemical) was intraperitoneally administered. After 30 minutes fromthe administration, the rats were subjected to isoflurane inhalationalanesthetic using a general anesthesia apparatus for experimentalanimals. Under isoflurane anesthesia, the rats were immobilized to abrain stereotaxic instrument. The skin on the head was incised with asurgical scalpel to expose the skull. The coordinates of the bregma usedas the origin (AP: 0, ML: 0, DV: 0) was determined, and the coordinatesof the right medial forebrain bundle (AP: -4.4 mm, ML: 1.5 mm, DV: 7.8mm from bregma) were measured. After inserting an injection tube foradministration at the measured coordinates, 6-OHDA (9 μg/4 μL;Sigma-Aldrich) inducing dopaminergic denervation was topically injected.After 2 weeks from surgery, apomorphine hydrochloride hemihydrate (0.5mg/kg; Wako Pure Chemical) was subcutaneously administered, and therotation movement to the opposite side from the 6-OHDA injected site wasobserved. Rats with 7 rotations or more per minute were used as ratstreated on one side with 6-OHDA.

To make a PD-LID model, a mixture of levodopa methyl ester hydrochloride(6 mg/kg; Sigma-Aldrich) dissolved in saline and benserazidehydrochloride (15 mg/kg; Sigma-Aldrich) (hereinafter, also referred toas “levodopa containing solution”) was intraperitoneally administeredonce daily to 6-OHDA-lesioned rats. The levodopa containing solution wasrepeated administered for 3 weeks or longer to observe and evaluate thebehavior. The behavior was observed and evaluated in a transparentacrylic cage for 1 minute every 20 minutes after 20 minutes from theintraperitoneal administration of the levodopa containing solution, upuntil after 3 hours from administration. Observation of behavior wasclassified into Limb AIMs (involuntary bending or stretching of frontlimbs on the opposite side of the disorder, opening/closing of hands, upand down movement of the wrist, chorea-like tremor, dystonia-likestiffening), Axial AIMs (twisting of the upper body/neck to the oppositeside of the disorder, losing balance and falling, or maintaining anunstable posture), Orolingual AIMs (trembling of the jaw or violentlysticking out the tongue forward), and Locomotive behavior (rotationalbehavior to the other side of the destruction), and was given a scorefrom 0 to 4 (0: none, 1: less than 30 seconds of manifestation, 2: 30seconds or more of manifestation, 3: constantly, but stopped with astimulus such as sound, and 4: constant manifestation, which does notstop with a stimulus such as sound). The sum of the scores for LimbAIMs, Axial AIMs, and Orolingual AIMs in 3 hours was used as the totalAIMs score. Individuals with a total AIMs score of less than 10 wereexcluded from the test as not manifesting a dyskinesia-like symptom. Thebehavior was observed and evaluated before the drug evaluation date. Therats were assigned to each dosing group by using the 3 hour AIMs score,Locomotive behavior score, and rat body weight as indicators, which wereused for evaluation of drugs.

(Transdermal Administration (Condition 1))

When evaluating a tape agent, the hair on the abdominal region of ratswas shaved before the evaluation date. The tape agent of formulation 2was applied to the abdominal regions of rats on the evaluation date at60 cm²/kg (37 mg/kg). After 4 hours from application, a levodopacontaining solution was intraperitoneally administered to observe andevaluate the behavior. Individuals with 50% or more of the tape agentcoming off during the test were excluded from analysis. After thecompletion of observation and evaluation of behavior, plasma wascollected to analyze the plasma tandospirone concentration.

(Transdermal Administration (Condition 2))

When evaluating a tape agent under stratum corneum stripping conditions(tandospirone high exposure conditions), stripping was performed 10times at the abdominal region of rats using a transpore surgical tape(3M) on the evaluation date, and a tape agent of formulation 3 was thenapplied at 60 cm²/kg (45 mg/kg). After 4 hours from application, alevodopa containing solution was intraperitoneally administered toobserve and evaluate the behavior. Individuals with 50% or more of thetape agent coming off during the test were excluded from analysis. Afterthe completion of observation and evaluation of behavior, plasma wascollected to analyze the plasma tandospirone concentration.

When evaluating dyskinesia-like symptoms, the sum of the Limb AIMs,Axial AIMs, and Orolingual AIMs at each evaluation point was used as theAIMs score. Statistical analysis on test results was performed byWilcoxon rank sum test using the total AIMs score, which is the sum ofAIMs scores for 3 hours, and total AIMs score in 100 to 180 minutes asparameters. ** indicates p<0.01, meaning that there is a significantdifference compared to the placebo tape agent application group. Theresults in the drawings are indicated in terms of mean value±standarderror.

(Results)

When tandospirone was transdermally absorbed by applying a tandospironetape agent (formulation 2: drug dosage of 37 mg/kg) via transdermaladministration (condition 1), the total AIMs score was 12.6. Compared toapplication of a placebo tape agent without tandospirone, the total AIMsscore decreased 17.7, so that a significant improvement was observed indyskinesia-like symptoms (FIGS. 2-A and B). Further, a cleardyskinesia-like symptom (mean AIMs score of 2 or greater) was notobserved for the placebo tape agent application group or thetandospirone tape agent application group at 120 to 140 minutes afterlevodopa administration. A significant difference was not found betweenthe two groups in the total AIMs score in 100 to 180 minutes (FIG. 2-C).The mean value of plasma tandospirone concentrations measured after thecompletion of observation and evaluation of behavior was 71.8 ng/mL.

When a high exposure tandospirone was transdermally absorbed by applyinga tandospirone tape agent (formulation 3: drug dosage of 45 mg/kg) understratum corneum stripping conditions via transdermal administration(condition 2), the total AIMs score was 5.8. Compared to application ofa placebo tape agent without tandospirone, the total AIMs scoredecreased 27.1, so that a significant improvement was observed indyskinesia-like symptoms. A higher effect of improvement was observedunder administration condition 2 than under administration condition 1(FIGS. 3-A and B). Further, a clear dyskinesia-like symptom (mean AIMsscore of 2 or greater) was not observed for the placebo tape agentapplication group or the tandospirone tape agent application group at120 to 140 minutes after levodopa administration under stratum corneumstripping conditions. A significant difference was not found between thetwo groups in the total AIMs score in 100 to 180 minutes (FIG. 3-C). Themean value of plasma tandospirone concentrations measured after thecompletion of observation and evaluation of behavior was 269 ng/mL. Themean value of plasma tandospirone concentration under administrationcondition 2 was 3 times or higher than that under administrationcondition 1.

In view of the above results, tandospirone transdermally administeredformulations improved PD-LID symptoms without a rebound symptom.

Further, it was found that the effect on PD-LID and anxiolytic action oftandospirone is exerted at the same dosage in a non-clinical model. Theanxiolytic action was evaluated using a rat Vogel conflict test model,and the effect on PD-LID was evaluated in 6-OHDA-lesioned rats.Therefore, the therapeutic effect in the invention is exerted at thesame blood concentration as tandospirone citrate tablets (Sedieltablets) commercially available as anxiolytic drugs.

Example 3 Evaluation of Dyskinesia Improving Effect Upon ContinuousSubcutaneous Infusion of Tandospirone

The efficacy of tandospirone on dyskinesia-like symptoms was evaluatedby continuous subcutaneous infusion of tandospirone to PD-LID ratmodels.

(Testing Method)

As in Example 2, a levodopa containing solution was repeatedadministered to 6-OHDA-lesioned rats for 3 weeks or longer to observeand evaluate the behavior. The behavior was observed and evaluatedbefore the drug evaluation date. The rats were assigned to each dosinggroup by using the 3 hour AIMs score, Locomotive behavior score, and ratbody weight as indicators, which were used for evaluation of drugs.However, individuals with a total AIMs score of less than 10 wereexcluded from the test as lacking manifestation of a dyskinesia-likesymptom. Individuals with a body weight deviating 10% or more from themean body weight were also excluded from the test to minimize variationin the dosage for each individual.

Tandospirone (free form) was dissolved in 1 M hydrochloric acid (NacalaiTesque) and diluted with saline and adjusted to 0.05, 0.25, or 1.25mg/kg/hour. The prepared solution was used after injection into anALZET® Osmotic Pump MODEL 2ML1 (9.68 μL/hour; DURECT).

An osmotic pump injected with tandospirone or solvent was implantedunder the skin of rats in each group with n=6. After 4 hours, a levodopacontaining solution was administered to observe and evaluate thebehavior. After the observation and evaluation of behavior, blood wascollected from rats in the tandospirone administration group to analyzethe plasma tandospirone concentration.

The results in the drawings are indicated in terms of meanvalue±standard error. The test results were statistically analyzed bycomparison with the solvent administration group by Steel test using thetotal AIMs score in 3 hours and the total AIMs score in 100 to 180minutes as parameters. * indicates p<0.05, meaning that there is asignificant difference.

(Results)

Continuous subcutaneous infusion of tandospirone dose-dependentlyimproved dyskinesia-like symptoms, and significant improvement wasobserved at 1.25 mg/kg/hour (FIGS. 4-A and B). A clear dyskinesia-likesymptom (mean AIMs score of 2 or greater) was not found in both thesolvent administration group and the tandospirone administration groupat 120 to 140 minutes after levodopa administration. Furthermore, thetotal AIMs score dose-dependently decreased by continuous subcutaneousinfusion of tandospirone, and a significant improvement was observed at1.25 mg/kg/hour in the total AIMs score in 100 to 180 minutes (FIG.4-C). The mean value of plasma tandospirone concentration measured afterthe completion of the observation and evaluation of behavior was 23.5ng/mL at 0.05 mg/kg/hour, 119 ng/mL at 0.25 mg/kg/hour, and 541 ng/mL at1.25 mg/kg/hour.

In view of the results, continuous subcutaneous infusion of tandospironedose-dependently improved dyskinesia-like symptoms. The administrationdid not lead to a rebound symptom at any of the dosages.

Example 4 Evaluation of Long-Term Dyskinesia Improving Effect ofContinuous Subcutaneous Infusion of Tandospirone

The sustainability of efficacy of tandospirone on dyskinesia-likesymptoms was evaluated by continuous subcutaneous infusion oftandospirone to PD-LID rat model over 2 weeks.

(Testing Method)

A levodopa containing solution was repeatedly administered to6-OHDA-lesioned rats for 3 weeks or more to observe and evaluate thebehavior in the same manner as Example 2. Individuals with a total AIMsscore of less than 15 were excluded from the test as not manifesting adyskinesia-like symptom. The behavior was observed and evaluated beforethe drug evaluation date. The rats were assigned to each dosing group byusing the 3 hour AIMs score, Locomotive behavior score, and rat bodyweight as indicators, which were used for evaluation of drugs.

Tandospirone citrate was dissolved into 1 M hydrochloric acid (NacalaiTesque) and diluted with saline and adjusted to a concentration of 60mg/mL (concentration of citrate). The prepared solution was used afterinjection into an ALZET® Osmotic Pump MODEL 2ML2 (4.53 μL/hour; DURECT)for releasing a drug solution at a stable rate for 2 weeks.

An osmotic pump injected with tandospirone citrate or solvent wasimplanted under the skin of rats in each group with n=8. After 4 hours,a levodopa containing solution was administered to observe and evaluatethe behavior (day 0 of implanting the pump). Repeat administration ofonce daily levodopa containing solution was continued thereafter. Thebehavior was also observed and evaluated on day 13 of implanting thepump. After each observation and evaluation of behavior, blood wascollected from half of the rats (n=4) in the tandospirone administrationgroup to analyze the plasma tandospirone concentration.

The results in the drawings are indicated in terms of meanvalue±standard error of the total AIMs scores in 3 hours. The testresults were statistically analyzed using Wilcoxon rank sum test usingthe total AIMs score as a parameter. ** indicates p<0.01, meaning thatthere is a significant difference compared to the solvent administrationgroup.

(Results)

Significant improvement in dyskinesia-like symptoms was observedcompared to the solvent group on day 0 of implanting the pump fromcontinuous subcutaneous infusion of tandospirone citrate (60 mg/mL: mean0.78 mg/kg/hour as tandospirone citrate) (FIG. 5-A). The mean value ofthe plasma tandospirone concentrations (value converted in terms of freeform) measured after the completion of observation and evaluation ofbehavior was 281 ng/mL. A significant improvement in dyskinesia-likesymptoms relative to the solvent group was also observed on day 13 ofimplanting the pump (FIG. 5-B). The mean value of the plasmatandospirone concentrations (value converted in terms of free form)measured after the completion of observation and evaluation of behaviorwas 143 ng/mL.

In view of the results, the effect of improving PD-LID symptoms wassustained even after continuous subcutaneous infusion of tandospironefor 13 days.

Example 5 Evaluation of the Effect Of Continuous Subcutaneous Infusionof Tandospirone on Prevention/Suppression of the Manifestation ofDyskinesia

Dyskinesia-like abnormal involuntary movement is manifested whenlevodopa is repeatedly administered to 6-OHDA-lesioned rats. In thisregard, the effect of tandospirone on preventing the manifestation ofdyskinesia-like symptoms was evaluated by subcutaneous sustainedadministration of tandospirone from immediately after starting therepeated administration of levodopa.

(Testing Method)

Tandospirone citrate was dissolved into 1 M hydrochloric acid (NacalaiTesque) and diluted with saline and adjusted to a concentration of 60mg/mL or 30 mg/mL. The prepared solution was used after injection intoan ALZET® Osmotic Pump MODEL 2ML2 (4.53 μL/hour; DURECT).

6-OHDA-lesioned rats were assigned to each administration group usingthe number of apomorphine hydrochloride hemihydrate induced rotationsand body weight as indicators. An osmotic pump injected withtandospirone citrate or solvent was implanted under the skin of rats onthe day after starting repeated administration of a levodopa containingsolution with the same composition as Example 2. The behavior wasobserved and evaluated using the same method as Example 2 on day 3, 5,9, and 15 after starting the repeated administration of levodopa. Theosmotic pump implanted subcutaneously was retrieved after theobservation and evaluation of behavior on day 15. The behavior was alsoobserved and evaluated on the following day (day 16 of repeatedadministration of levodopa).

The results in the drawings are indicated in terms of meanvalue±standard error of the total AIMs scores in 3 hours. The testresults were statistically analyzed by comparison with the solventadministration group using Steel test with the total AIMs score on day16 of repeated levodopa administration as the parameter. * indicatesp<0.05 and ** indicates p<0.01, meaning that there is a significantdifference compared to the solvent administration group.

(Results)

Continuous subcutaneous infusion of tandospirone citrate (30 mg/mL: meanof 0.41 mg/kg/hour or 60 mg/mL: mean of 0.83 mg/kg/hour) suppressed theincrease in total AIMs score associated with repeated administration oflevodopa compared to the solvent group (FIG. 6-A). The total AIMs scorewas significantly lower in the group administered with tandospironecitrate compared to the solvent group on the day after the completion oftandospirone citrate administration (FIG. 6-B).

In view of the results, continuous subcutaneous infusion of tandospironeprevented onset of PD-LID, and the effect thereof was also sustained tothe day after the final dose of tandospirone.

Comparative Example 1 Evaluation of Oral Administration of Tandospironeon Dyskinesia Symptoms

(Testing Method)

The behavior was observed and evaluated using the same method as Example2. Tandospirone citrate was suspended in 0.5% methylcellulose solutionand orally administered to rats. After 5 minutes, a levodopa containingsolution was intraperitoneally administered, and the behavior wasobserved and evaluated. The results in the drawings are indicated interms of mean value±standard error. The test results were statisticallyanalyzed by comparison with the solvent administration group by Steeltest using the total AIMs score in 3 hours and total AIMs score in 100to 180 minutes as parameters. * indicates p<0.05, meaning that there isa significant difference.

(Results)

(1) Dyskinesia-Like Symptom

In the tandospirone citrate (10, 30, or 100 mg/kg as citrateconcentration) orally administered groups, a significant change in thetotal AIMs score was not observed in comparison to the solventadministration group (FIGS. 7 and 8-A and B). The results suggest thatthe PD-LID cannot be improved with a tandospirone oral administrationformulation.

At 120 to 140 minutes after levodopa administration, dyskinesia-likesymptoms subsided in the solvent administration group, but a cleardyskinesia-like symptom (mean AIMs score of 2 or greater) was observedin the tandospirone citrate oral administration group (30 or 100 mg/kg).Furthermore, when the solvent administration group and tandospironecitrate oral administration group were compared using the total AIMsscore in 100 to 180 minutes as the indicator, a significant increase inthe total AIMs score was observed in the tandospirone citrate oraladministration group (30 or 100 mg/kg) in comparison to the solventadministration group (FIGS. 7 and 8-C). The result suggests thepotential of manifestation of a phenomenon with delayed manifestationand exacerbation of dyskinesia-like symptoms (rebound symptom ofdyskinesia) in a formulation for oral administration of tandospirone.

In view of the above, an improvement in dyskinesia symptoms was notobserved in PD-LID rat models in the tandospirone oral administrationgroup (Table 3-(i)). A rebound symptom of dyskinesia was observed inhigh dosage oral administration group (Table 3-(ii)). In view of theresults, oral administration of tandospirone has an insufficient effectof improving dyskinesia, and has a risk of manifestation of a reboundsymptom. Therefore, combined therapy with a levodopa formulation ispossibly unsuitable.

TABLE 3 Comparison of dyskinesia-like symptom scores for transdermal andoral administration (i) Indicator of degree of (ii) Indicator Dosageimprovement in of rebound (mg/kg) dyskinesia symptom of Conditionsymptom dyskinesia Transdermal 37 Improvement No effect administration(No stripping) 17.7** −0.1 (Condition 1) (Example 2) Transdermal 45Improvement No effect administration (With stripping) 27.1** 0.9(Condition 2) (Example 2) Oral 6.7 No improvement Exacerbatingadministration −3.1 trend (Comparative −3.5 Example 1) Oral 20 Noimprovement Exacerbation administration −6.5(FIG. 7) −9.1*(FIG. 7)(Comparative −8.6(FIG. 8) −8.5*(FIG. 8) Example 1) Oral 67 Noimprovement Exacerbation administration 2.9 −10.1* (Comparative Example1)

The dosage was described as a numerical value converted in terms oftandospirone free form. The difference in total AIMs score in threehours (#1) is used as an indicator of a degree of improvement indyskinesia symptoms, and the difference in total AIMs score in 100 to180 minutes (#2) is used as an indicator of a rebound symptom ofdyskinesia.

-   (#1) Difference in total AIMs score in 3 hours=(total AIMs score for    placebo tape agent or solvent administration group)−(total AIMs    score for tandospirone administration group)-   (#2) Difference in total AIMs score in 100 to 180 minutes=(total    AIMs score in 100 to 180 minutes for placebo tape agent or solvent    administration group)−(total AIMs score in 100 to 180 minutes for    tandospirone administration group)-   **: there is a significant difference (p<0.01), *: there is a    significant difference (p<0.05)

As shown in Table 3, a significant difference in improvement of levodopainduced dyskinesia symptoms was not found with oral administration, buta significant improvement thereof was found with transdermaladministration.

Oral administration was also newly found to have a rebound symptom ofdyskinesia, so that therapy by oral administration of tandospirone wasfound to be undesirable. Meanwhile, a rebound symptom of dyskinesia wasnot observed for transdermal administration.

In view of the above, the therapeutic effect of tandospirone oraladministration on levodopa induced dyskinesia symptoms is limited,suggesting that tandospirone transdermal administration is preferable.

Comparative Example 2 Evaluation of Tandospirone Metabolite onDyskinesia Symptom

The effect of a tandospirone metabolite 1-(2-Pyrimidyl)piperazine(hereinafter, also referred to as “1-PP”) on dyskinesia-like symptomswas evaluated.

(Testing Method)

The behavior was observed and evaluated using the same method in Example2. 1-PP dihydrochloride (Tokyo Chemical Industry) was dissolved insaline and subcutaneously administered to rats. After 5 minutes, alevodopa containing solution was intraperitoneally administered toobserve and evaluate the behavior. The results in the drawings areindicated in terms of mean value±standard error. The test results werestatistically analyzed by comparison with the solvent administrationgroup by Steel test by using the total AIMs score in 3 hours and totalAIMs score in 100 to 180 minutes as parameters.

(Results)

A significant change in the total AIMs score was not found in the 1-PPdihydrochloride (10 or 30 mg/kg) subcutaneous administration group,relative to the solvent administration group (FIGS. 10-A and B).

At 120 to 140 minutes after administration of levodopa, a cleardyskinesia-like symptom (mean AIMs score of 2 or greater) was observedin the 1-PP dihydrochloride subcutaneous administration group (10 or 30mg/kg). When the solvent administration group and the 1-PPdihydrochloride administration group were compared by using the totalAIMs score in 100 to 180 minutes as an indicator, an increasing trend inthe total AIMs score, albeit not significant, was observed in the 1-PPdihydrochloride administration group relative to the solventadministration group (FIG. 10-C). The result suggests the potential oftandospirone metabolite 1-PP inducing a rebound symptom of dyskinesia.

The result suggests the potential of a rebound symptom of dyskinesiaunder administration conditions generating the tandospirone metabolite1-PP. In other words, for tandospirone, a method of administration thatcan suppress the generation of 1-PP has less effect on rebound symptomsof dyskinesia and is preferable.

Example 6 Demonstration in Clinical Protocol

The effect of improving PD-LID of the compound of the invention or thecombined drug of the invention can be confirmed by a clinical study inaccordance with the method described in the following Reference Document1 (amantadine P3) as clinical study with a suitable design that canevaluate PD-LID (Reference Document 1: JAMA Neurology 2017; 74 (8)941-949; Reference Document 2: Movement Disorders 2015; 30 (19)1343-1350).

More specifically, the effect of improving PD-LID can be confirmed by,for example, administering the tandospirone or a pharmaceuticallyacceptable salt or prodrug thereof of the invention or a combined drugof the invention for a certain dosing period (examples thereof include,but are not limited to, 8 to 12 weeks) in 20 years old or older patientsdiagnosed as having Parkinson's disease and comparing the period ofdyskinesia manifestation based on a patient diary or score such asUPDRS, UDysRS, CDRS, or AIMS before and after the dosing period or thelike.

The conditions such as the target patient, dosing period, dosage ofagent, and evaluation method can be appropriately changed in the abovetest.

(Note)

As disclosed above, the present invention is exemplified by the use ofits preferred embodiments. However, it is understood that the scope ofthe present invention should be interpreted solely based on the Claims.It is also understood that any patent, any patent application, and anyother references cited herein should be incorporated herein by referencein the same manner as the contents are specifically described herein.

INDUSTRIAL APPLICABILITY

A parenterally administered tandospirone formulation is useful as atherapeutic drug that improves PD-LID.

1-21. (canceled)
 22. A method for treating or improving the exacerbationin quality of response to levodopa therapy of a Parkinson's diseasepatient with dyskinesia in a subject, comprising parenterallyadministering to the subject an effective amount of tandospirone or apharmaceutically acceptable salt thereof.
 23. The method of claim 22,wherein the parenteral administration is selected from transdermaladministration, intradermal administration, subcutaneous administration,intramuscular administration, and a combination thereof.
 24. The methodof claim 22, wherein the parenteral administration comprises transdermaladministration.
 25. The method of claim 22, wherein the tandospirone ora pharmaceutically acceptable salt thereof is provided as atransdermally administered formulation.
 26. The method of claim 22,wherein the tandospirone or a pharmaceutically acceptable salt thereofis provided as an adhesive formulation.
 27. The method of claim 25,wherein the transdermally administered formulation is a tape/patch. 28.The method of claim 22, wherein a drug dosage of the tandospirone or apharmaceutically acceptable salt thereof is 0.1 to 100 mg per day as afree form of tandospirone.
 29. The method of claim 22, wherein an amountof drug penetration for the tandospirone or a pharmaceuticallyacceptable salt thereof is 0.1 to 20 mg per day as a free form oftandospirone.
 30. The method of claim 22, wherein the tandospirone or apharmaceutically acceptable salt thereof is provided as a transdermallyadministered formulation, and a total applied area per dose is 1 to 100cm².
 31. The method of claim 22, wherein the tandospirone or apharmaceutically acceptable salt thereof is an adjunct of levodopa. 32.The method of claim 22, wherein the tandospirone or a pharmaceuticallyacceptable salt thereof is used with levodopa as the fixed-dosecombination or concomitantly as separate formulations.
 33. Apharmaceutical composition for use in treating or preventing Parkinson'sdisease without accompanying or by minimizing PD-LID in a subject,comprising an effective amount of tandospirone or a pharmaceuticallyacceptable salt thereof and (1) an effective amount of levodopa or (2)levodopa and a metabolizing enzyme inhibitor of levodopa, wherein thetandospirone or a pharmaceutically acceptable salt thereof is an adjunctof levodopa, and wherein the composition is suitable for parenteraladministration.
 34. The pharmaceutical composition of claim 33, whereinthe tandospirone or a pharmaceutically acceptable salt thereof and the(1) or (2) are suitable for simultaneous administration or separateadministration at different times.